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Khan A, Dawar P, De S. Thiourea compounds as multifaceted bioactive agents in medicinal chemistry. Bioorg Chem 2025; 158:108319. [PMID: 40058221 DOI: 10.1016/j.bioorg.2025.108319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/19/2025]
Abstract
Microbial resistance (MR) and cancer are global healthcare pitfalls that have caused millions of deaths and pose a significant pharmaceutical challenge, with clinical cases increasing. Thioureas are preferred structures in medicinal chemistry, chemosensors, and organic synthesis platforms. In fact, thiourea (TU) moieties serve as a common framework for several medications and bioactive substances, demonstrating a wide range of therapeutic and pharmacological accomplishments. The integration of the thiourea moiety into a diverse range of organic molecules has resulted in very flexible compounds with widespread uses in medicinal chemistry. Moreover, for over a century, TU and its metal complexes have been characterized for their biological activity. Finally, we provide an assessment and future outlook of different organo-thiourea derivatives, from the very beginning to the most recent discoveries in medicinal activity.
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Affiliation(s)
- Adeeba Khan
- Department of Chemistry, Organic Chemistry Lab, Manipal University Jaipur, Jaipur, Rajasthan 303007, India
| | - Palak Dawar
- Department of Chemistry, Organic Chemistry Lab, Manipal University Jaipur, Jaipur, Rajasthan 303007, India
| | - Suranjan De
- Department of Chemistry, Organic Chemistry Lab, Manipal University Jaipur, Jaipur, Rajasthan 303007, India.
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Motyl JA, Gromadzka G, Czapski GA, Adamczyk A. SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms. Int J Mol Sci 2024; 25:12079. [PMID: 39596147 PMCID: PMC11593367 DOI: 10.3390/ijms252212079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/30/2024] [Accepted: 11/08/2024] [Indexed: 11/28/2024] Open
Abstract
Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation-and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms-it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms.
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Affiliation(s)
- Joanna Agata Motyl
- Department of Hybrid Microbiosystems Engineering, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, Ks. Trojdena 4 St., 02-109 Warsaw, Poland;
| | - Grażyna Gromadzka
- Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Wóycickiego 1/3, 01-938 Warsaw, Poland;
| | - Grzegorz Arkadiusz Czapski
- Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
| | - Agata Adamczyk
- Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
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Dekundy A, Pichler G, El Badry R, Scheschonka A, Danysz W. Amantadine for Traumatic Brain Injury-Supporting Evidence and Mode of Action. Biomedicines 2024; 12:1558. [PMID: 39062131 PMCID: PMC11274811 DOI: 10.3390/biomedicines12071558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions.
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Affiliation(s)
- Andrzej Dekundy
- Merz Therapeutics GmbH, Eckenheimer Landstraße 100, 60318 Frankfurt am Main, Germany; (A.D.); (A.S.)
| | - Gerald Pichler
- Department of Neurology, Albert-Schweitzer-Hospital Graz, Albert-Schweitzer-Gasse 36, 8020 Graz, Austria;
| | - Reda El Badry
- Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut University, Assiut 71526, Egypt;
| | - Astrid Scheschonka
- Merz Therapeutics GmbH, Eckenheimer Landstraße 100, 60318 Frankfurt am Main, Germany; (A.D.); (A.S.)
| | - Wojciech Danysz
- Danysz Pharmacology Consulting, Vor den Gärten 16, 61130 Nidderau, Germany
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Hu X, Li Y, Qu H, He C, Chen Z, Zhan M, Du Y, Wang H, Chen W, Sun L, Ning X. No genetic link between Parkinson's disease and SARS-CoV-2 infection: a two-sample Mendelian randomization study. Front Neurol 2024; 15:1393888. [PMID: 39006236 PMCID: PMC11239547 DOI: 10.3389/fneur.2024.1393888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 06/13/2024] [Indexed: 07/16/2024] Open
Abstract
Objective Existing literature has not clearly elucidated whether SARS-CoV-2 infection increases the incidence of Parkinson's disease or if Parkinson's disease patients are more susceptible to the effects of SARS-CoV-2 infection. To clarify the issue, this study employs a genetic epidemiological approach to investigate the association. Methods This study utilizes a two-sample Mendelian randomization analysis. The primary analysis employs the inverse variance-weighted (IVW) method, supplemented by secondary analyses including MR-Egger regression, weighted median, IVW radial method, and weighted mode, to evaluate the bidirectional causal relationship between Parkinson's disease and SARS-CoV-2 infection. Results IVW results showed no genetic causality between SARS-CoV-2 susceptibility, hospitalization rate and severity and Parkinson's disease. (IVW method: p = 0.408 OR = 1.10 95% CI: 0.87 ~ 1.39; p = 0.744 OR = 1.11 95% CI: 0.94 ~ 1.09; p = 0.436 OR = 1.05 95% CI: 0.93 ~ 1.17). Parkinson's disease was not genetically associated with susceptibility to new crown infections, hospitalization rates, and severity (IVW method: p = 0.173 OR = 1.01 95% CI: 0.99 ~ 1.03; p = 0.109 OR = 1.05 95% CI: 0.99 ~ 1.12; p = 0.209 OR = 1.03 95% CI: 0.99 ~ 1.07). MR-Egger regression, weighted median, IVW radial method, and weighted mode results are consistent with the results of the IVW method. Conclusion This study does not support a genetic link between Parkinson's disease and SARS-CoV-2 infection, and the association observed in previous cohort studies and observational studies may be due to other confounding factors.
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Affiliation(s)
- Xiaohua Hu
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yutong Li
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Hua Qu
- National Research Center for Cardiovascular Diseases of Traditional Chinese, Beijing, China
- Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing, China
| | - Chunying He
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiyan Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Min Zhan
- Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing, China
| | - Yida Du
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Huan Wang
- Graduate School, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenjie Chen
- Ezhou Traditional Chinese Medicine Hospital, Ezhou, China
| | - Linjuan Sun
- Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing, China
| | - Xia Ning
- Xiyuan Hospital, Chinese Academy of Traditional Chinese Medicine, Beijing, China
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Li H, Qian J, Wang Y, Wang J, Mi X, Qu L, Song N, Xie J. Potential convergence of olfactory dysfunction in Parkinson's disease and COVID-19: The role of neuroinflammation. Ageing Res Rev 2024; 97:102288. [PMID: 38580172 DOI: 10.1016/j.arr.2024.102288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/28/2024] [Accepted: 03/30/2024] [Indexed: 04/07/2024]
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder that affects 7-10 million individuals worldwide. A common early symptom of PD is olfactory dysfunction (OD), and more than 90% of PD patients suffer from OD. Recent studies have highlighted a high incidence of OD in patients with SARS-CoV-2 infection. This review investigates the potential convergence of OD in PD and COVID-19, particularly focusing on the mechanisms by which neuroinflammation contributes to OD and neurological events. Starting from our fundamental understanding of the olfactory bulb, we summarize the clinical features of OD and pathological features of the olfactory bulb from clinical cases and autopsy reports in PD patients. We then examine SARS-CoV-2-induced olfactory bulb neuropathology and OD and emphasize the SARS-CoV-2-induced neuroinflammatory cascades potentially leading to PD manifestations. By activating microglia and astrocytes, as well as facilitating the aggregation of α-synuclein, SARS-CoV-2 could contribute to the onset or exacerbation of PD. We also discuss the possible contributions of NF-κB, the NLRP3 inflammasome, and the JAK/STAT, p38 MAPK, TLR4, IL-6/JAK2/STAT3 and cGAS-STING signaling pathways. Although olfactory dysfunction in patients with COVID-19 may be reversible, it is challenging to restore OD in patients with PD. With the emergence of new SARS-CoV-2 variants and the recurrence of infections, we call for continued attention to the intersection between PD and SARS-CoV-2 infection, especially from the perspective of OD.
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Affiliation(s)
- Hui Li
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China
| | - Junliang Qian
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China
| | - Youcui Wang
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China
| | - Juan Wang
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China
| | - Xiaoqing Mi
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China
| | - Le Qu
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China
| | - Ning Song
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China.
| | - Junxia Xie
- Institute of Brain Science and Disease, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, China.
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Cheyne I, Gopinath VS, Muppa N, Armas AE, Gil Agurto MS, Akula SA, Nagpal S, Yousaf MS, Haider A. The Neurological Implications of COVID-19: A Comprehensive Narrative Review. Cureus 2024; 16:e60376. [PMID: 38887342 PMCID: PMC11181960 DOI: 10.7759/cureus.60376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/15/2024] [Indexed: 06/20/2024] Open
Abstract
The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 revealed a huge number of problems as well as discoveries in medicine, notably, regarding the effects of the virus on the central nervous system (CNS) and peripheral nervous system (PNS). This paper is a narrative review that takes a deep dive into the complex interactions between COVID-19 and the NS. Therefore, this paper explains the broad range of neurological manifestations and neurodegenerative diseases caused by the virus. It carefully considers the routes through which SARS-CoV-2 reaches the NS, including the olfactory system and of course, the hematogenous route, which are also covered when discussing the virus's direct and indirect mechanisms of neuropathogenesis. Besides neurological pathologies such as stroke, encephalitis, Guillain-Barré syndrome, Parkinson's disease, and multiple sclerosis, the focus area is also given to the challenges of making diagnosis, treatment, and management of these conditions during the pandemic. The review also examines the strategic and interventional approaches utilized to prevent these disorders, as well as the ACE2 receptors implicated in the mediation of neurological effects caused by COVID-19. This detailed overview, which combines research outputs with case data, is directed at tackling this pandemic challenge, with a view toward better patient care and outcomes in the future.
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Affiliation(s)
- Ithamar Cheyne
- Critical Care, Medical University of Warsaw, Warsaw, POL
| | | | - Neeharika Muppa
- School of Medicine, St. George's University, St. George's, GRD
| | - Angel Emanuel Armas
- Internal Medicine, Cardiac Arrhythmia Service, Harvard Medical School, Boston, USA
| | | | - Sai Abhigna Akula
- Internal Medicine, School of Medicine, St. George's University, St. George's, GRD
| | - Shubhangi Nagpal
- Internal Medicine, Guru Gobind Singh Government Hospital, New Delhi, IND
| | | | - Ali Haider
- Allied Health Sciences, The University of Lahore, Gujrat Campus, Gujrat, PAK
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de Almeida Marques DP, Andrade LAF, Reis EVS, Clarindo FA, Moraes TDFS, Lourenço KL, De Barros WA, Costa NEM, Andrade LMD, Lopes-Ribeiro Á, Coêlho Maciel MS, Corrêa-Dias LC, de Almeida IN, Arantes TS, Litwinski VCV, de Oliveira LC, Serafim MSM, Maltarollo VG, Guatimosim SC, Silva MM, Tsuji M, Ferreira RS, Barreto LV, Barbosa-Stancioli EF, da Fonseca FG, De Fátima Â, Coelho-Dos-Reis JGA. New anti-SARS-CoV-2 aminoadamantane compounds as antiviral candidates for the treatment of COVID-19. Virus Res 2024; 340:199291. [PMID: 38065303 PMCID: PMC10733093 DOI: 10.1016/j.virusres.2023.199291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
Here, the antiviral activity of aminoadamantane derivatives were evaluated against SARS-CoV-2. The compounds exhibited low cytotoxicity to Vero, HEK293 and CALU-3 cells up to a concentration of 1,000 µM. The inhibitory concentration (IC50) of aminoadamantane was 39.71 µM in Vero CCL-81 cells and the derivatives showed significantly lower IC50 values, especially for compounds 3F4 (0.32 µM), 3F5 (0.44 µM) and 3E10 (1.28 µM). Additionally, derivatives 3F5 and 3E10 statistically reduced the fluorescence intensity of SARS-CoV-2 protein S from Vero cells at 10 µM. Transmission microscopy confirmed the antiviral activity of the compounds, which reduced cytopathic effects induced by the virus, such as vacuolization, cytoplasmic projections, and the presence of myelin figures derived from cellular activation in the face of infection. Additionally, it was possible to observe a reduction of viral particles adhered to the cell membrane and inside several viral factories, especially after treatment with 3F4. Moreover, although docking analysis showed favorable interactions in the catalytic site of Cathepsin L, the enzymatic activity of this enzyme was not inhibited significantly in vitro. The new derivatives displayed lower predicted toxicities than aminoadamantane, which was observed for either rat or mouse models. Lastly, in vivo antiviral assays of aminoadamantane derivatives in BALB/cJ mice after challenge with the mouse-adapted strain of SARS-CoV-2, corroborated the robust antiviral activity of 3F4 derivative, which was higher than aminoadamantane and its other derivatives. Therefore, aminoadamantane derivatives show potential broad-spectrum antiviral activity, which may contribute to COVID-19 treatment in the face of emerging and re-emerging SARS-CoV-2 variants of concern.
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Affiliation(s)
- Daisymara Priscila de Almeida Marques
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Luis Adan Flores Andrade
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Centro Tecnológico de Vacinas (CT Vacinas), Belo Horizonte, MG, Brazil
| | - Erik Vinicius Sousa Reis
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Felipe Alves Clarindo
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Thaís de Fátima Silva Moraes
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Karine Lima Lourenço
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Centro Tecnológico de Vacinas (CT Vacinas), Belo Horizonte, MG, Brazil
| | - Wellington Alves De Barros
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Nathália Evelyn Morais Costa
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lídia Maria de Andrade
- Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ágata Lopes-Ribeiro
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mariella Sousa Coêlho Maciel
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Laura Cardoso Corrêa-Dias
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Isabela Neves de Almeida
- Departamento de Análises Clínicas, Escola de Farmácia, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil; Laboratório de Micobacterioses, Faculdade de Medicina, Universidade Federal de, Minas Gerais, Belo Horizonte, MG, Brazil
| | - Thalita Souza Arantes
- Centro de Microscopia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Vivian Costa Vasconcelos Litwinski
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Leonardo Camilo de Oliveira
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Mateus Sá Magalhães Serafim
- Laboratório de Virus, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Vinicius Gonçalves Maltarollo
- Departamento de Produtos Farmacêuticos da Faculdade de Farmácia, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Silvia Carolina Guatimosim
- Departamento de Fisiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Mário Morais Silva
- Departamento de Fisiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Moriya Tsuji
- Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Rafaela Salgado Ferreira
- Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Luiza Valença Barreto
- Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, Belo Horizonte, MG, Brazil
| | - Edel Figueiredo Barbosa-Stancioli
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Flávio Guimarães da Fonseca
- Laboratório de Virologia Básica e Aplicada (LVBA), Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Centro Tecnológico de Vacinas (CT Vacinas), Belo Horizonte, MG, Brazil
| | - Ângelo De Fátima
- Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
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Rejdak K, Fiedor P, Bonek R, Łukasiak J, Chełstowski W, Kiciak S, Dąbrowski P, Gala‐Błądzińska A, Dec M, Papuć E, Zasybska A, Kaczor M, Grieb P, COV‐PREVENT Study Group. Amantadine in unvaccinated patients with early, mild to moderate COVID-19: A randomized, placebo-controlled, double-blind trial. Eur J Neurol 2024; 31:e16045. [PMID: 37584095 PMCID: PMC11235826 DOI: 10.1111/ene.16045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/24/2023] [Accepted: 08/08/2023] [Indexed: 08/17/2023]
Abstract
BACKGROUND AND PURPOSE Adamantanes were listed as an interesting option as an early intervention against COVID-19. We aimed to evaluate the effectiveness of amantadine in preventing the progression of COVID-19 and its neurological sequelae. METHODS Unvaccinated patients with confirmed SARS-CoV-2 infection within 5 days were enrolled. Subjects were randomized (50:50) to amantadine (AMD; 100 mg twice daily) or placebo (PLB) for 14 days. The Ordinal Scale for Clinical Improvement of the World Health Organization (OSCI-WHO) was the primary measure. Secondary endpoints included assessment for fatigue; depression, disorders of smell and taste, and sleepiness on Days 1 and 15. RESULTS We enrolled 99 patients (49 AMD and 50 PLB). Disease progression (OSCI-WHO = 4) was observed in 6% (AMD) and 8% (PLB) patients (p > 0.05) with further deterioration (OSCI-WHO〉4) in 0% (AMD) and 8% (PLB) patients (p > 0.05). Complete recovery on Day 15 was 60% higher in the AMD compared with the PLB group (p = 0.025). There was improvement in taste (AMD: p = 0.003; PLB: p = 0.0001) and smell (AMD: p = 0.005; PLB: p = 0.0004) but not in fatigue in both groups. Improvement was observed in the AMD (p = 0.010) but not in the PLB group (p = 0.058) when assessing depression as well as sleepiness (AMD: p = 0.0002; PLB: p = 0.341). There was one death in the PLB group (2.0%) and none in the AMD group (p > 0.05) until Day 210. Overall, the drug was well tolerated. CONCLUSION The central effects of amantadine on the nervous system with reduction of sleepiness and depression might have had a supportive effect on faster recovery in early COVID-19 patients.
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Affiliation(s)
- Konrad Rejdak
- Department of NeurologyMedical University of LublinLublinPoland
| | - Piotr Fiedor
- Department of General and Transplantation SurgeryMedical University of WarsawWarsawPoland
| | - Robert Bonek
- Department of Neurology and Clinical NeuroimmunologyRegional Specialist HospitalGrudziadzPoland
| | | | | | - Sławomir Kiciak
- Independent Voivodeship Hospital “Jana Bożego” in LublinLublinPoland
| | - Piotr Dąbrowski
- Independent Voivodeship Hospital “Jana Bożego” in LublinLublinPoland
| | - Agnieszka Gala‐Błądzińska
- Collegium MedicumUniversity of Rzeszów and St. Queen Jadwiga Clinical District Hospital No. 2RzeszówPoland
| | - Mateusz Dec
- SPZOZ Kalwaria ZebrzydowskaKalwaria ZebrzydowskaPoland
| | - Ewa Papuć
- Department of NeurologyMedical University of LublinLublinPoland
| | | | | | - Paweł Grieb
- Department of Experimental PharmacologyMossakowski Medical Research Institute, Polish Academy of SciencesWarsawPoland
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Chi M, Heutlinger O, Heffernan C, Sanger T, Marano R, Feaster W, Taraman S, Ehwerhemuepha L. Chronic Neurological Disorders and Predisposition to Severe COVID-19 in Pediatric Patients in the United States. Pediatr Neurol 2023; 147:130-138. [PMID: 37611407 DOI: 10.1016/j.pediatrneurol.2023.07.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 07/12/2023] [Accepted: 07/17/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND We investigated the association between chronic pediatric neurological conditions and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS This matched retrospective case-control study includes patients (n = 71,656) with chronic complex neurological disorders under 18 years of age, with laboratory-confirmed diagnosis of COVID-19 or a diagnostic code indicating infection or exposure to SARS-CoV-2, from 103 health systems in the United States. The primary outcome was the severity of coronavirus disease 2019 (COVID-19), which was classified as severe (invasive oxygen therapy or death), moderate (noninvasive oxygen therapy), or mild/asymptomatic (no oxygen therapy). A cumulative link mixed effects model was used for this study. RESULTS In this study, a cumulative link mixed effects model (random intercepts for health systems and patients) showed that the following classes of chronic neurological disorders were associated with higher odds of severe COVID-19: muscular dystrophies and myopathies (OR = 3.22; 95% confidence interval [CI]: 2.73 to 3.84), chronic central nervous system disorders (OR = 2.82; 95% CI: 2.67 to 2.97), cerebral palsy (OR = 1.97; 95% CI: 1.85 to 2.10), congenital neurological disorders (OR = 1.86; 95% CI: 1.75 to 1.96), epilepsy (OR = 1.35; 95% CI: 1.26 to 1.44), and intellectual developmental disorders (OR = 1.09; 95% CI: 1.003 to 1.19). Movement disorders were associated with lower odds of severe COVID-19 (OR = 0.90; 95% CI: 0.81 to 0.99). CONCLUSIONS Pediatric patients with chronic neurological disorders are at higher odds of severe COVID-19. Movement disorders were associated with lower odds of severe COVID-19.
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Affiliation(s)
- Megan Chi
- Children's Health of Orange County, Orange, California; Liberty University College of Osteopathic Medicine, Lynchburg, Virginia
| | - Olivia Heutlinger
- University of California-Irvine School of Medicine, Irvine, California
| | - Carly Heffernan
- University of California-Irvine School of Medicine, Irvine, California
| | - Terence Sanger
- Children's Health of Orange County, Orange, California; University of California-Irvine School of Medicine, Irvine, California
| | - Rachel Marano
- Children's Health of Orange County, Orange, California
| | | | - Sharief Taraman
- Children's Health of Orange County, Orange, California; University of California-Irvine School of Medicine, Irvine, California
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10
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Weis N, Bollerup S, Sund JD, Glamann JB, Vinten C, Jensen LR, Sejling C, Kledal TN, Rosenkilde MM. Amantadine for COVID-19 treatment (ACT) study: a randomized, double-blinded, placebo-controlled clinical trial. Clin Microbiol Infect 2023; 29:1313-1319. [PMID: 37353078 PMCID: PMC10284620 DOI: 10.1016/j.cmi.2023.06.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 06/25/2023]
Abstract
OBJECTIVES The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if pre-emptive treatment with amantadine for COVID-19 in non-hospitalized persons ≥40 years or adults with comorbidities was able to prevent disease progression and hospitalization. Primary outcomes were clinical status on day 14. METHODS Between 9 June 2021 and 27 January 2022, this randomized, double-blinded, placebo-controlled, single-centre clinical trial included 242 subjects with a follow-up period of 90 days. Subjects were randomly assigned 1:1 to either amantadine 100 mg or placebo twice daily for 5 days. The inclusion criteria were confirmed SARS-CoV-2 infection and at least one of (a) age ≥40 years, age ≥18 years and (b) at least one comorbidity, or (c) body mass index ≥30. The study protocol was published at www. CLINICALTRIALS gov (unique protocol #02032021) and at www.clinicaltrialregister.eu (EudraCT-number 2021-001177-22). RESULTS With 121 participants in each arm, we found no difference in the primary endpoint with 82 participants in the amantadine arm, and 92 participants in the placebo arm with no limitations to activities, respectively, and 25 and 37 with limitations to activities in the amantadine arm and the placebo arm, respectively. No participants in either group were admitted to hospital or died. The OR of having state severity increased by 1 in the amantadine group versus placebo was 1.8 (CI 1.0-3.3, [p 0.051]). On day 7, one participant was hospitalized in each group; throughout the study, this increased to five and three participants for amantadine versus placebo treatment (p 0.72). Similarly, on day 7, there was no difference in the status of oropharyngeal swabs. Most participants (108 in each group) were SARS-CoV-2 RNA positive (p 0.84). CONCLUSION We found no effect of amantadine on disease progression of SARS-CoV-2 infection.
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Affiliation(s)
- Nina Weis
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe Bollerup
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | - Jon Dissing Sund
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | - Jakob Borg Glamann
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | - Caroline Vinten
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | - Louise Riger Jensen
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | - Christoffer Sejling
- Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | | | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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11
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Low ZY, Wong KH, Wen Yip AJ, Choo WS. The convergent evolution of influenza A virus: Implications, therapeutic strategies and what we need to know. CURRENT RESEARCH IN MICROBIAL SCIENCES 2023; 5:100202. [PMID: 37700857 PMCID: PMC10493511 DOI: 10.1016/j.crmicr.2023.100202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/14/2023] Open
Abstract
Influenza virus infection, more commonly known as the 'cold flu', is an etiological agent that gives rise to recurrent annual flu and many pandemics. Dated back to the 1918- Spanish Flu, the influenza infection has caused the loss of many human lives and significantly impacted the economy and daily lives. Influenza virus can be classified into four different genera: influenza A-D, with the former two, influenza A and B, relevant to humans. The capacity of antigenic drift and shift in Influenza A has given rise to many novel variants, rendering vaccines and antiviral therapies useless. In light of the emergence of a novel betacoronavirus, the SARS-CoV-2, unravelling the underpinning mechanisms that support the recurrent influenza epidemics and pandemics is essential. Given the symptom similarities between influenza and covid infection, it is crucial to reiterate what we know about the influenza infection. This review aims to describe the origin and evolution of influenza infection. Apart from that, the risk factors entail the implication of co-infections, especially regarding the COVID-19 pandemic is further discussed. In addition, antiviral strategies, including the potential of drug repositioning, are discussed in this context. The diagnostic approach is also critically discussed in an effort to understand better and prepare for upcoming variants and potential influenza pandemics in the future. Lastly, this review encapsulates the challenges in curbing the influenza spread and provides insights for future directions in influenza management.
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Affiliation(s)
- Zheng Yao Low
- School of Science, Monash University Malaysia, 47500 Subang Jaya, Selangor, Malaysia
| | - Ka Heng Wong
- School of Science, Monash University Malaysia, 47500 Subang Jaya, Selangor, Malaysia
| | - Ashley Jia Wen Yip
- School of Science, Monash University Malaysia, 47500 Subang Jaya, Selangor, Malaysia
| | - Wee Sim Choo
- School of Science, Monash University Malaysia, 47500 Subang Jaya, Selangor, Malaysia
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12
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Zahra FT, Saeed A, Ahmed A, Ismail H, Ijaz MU, Albericio F. Synthesis of amantadine clubbed N-aryl amino thiazoles as potent urease, α-amylase & α-glucosidase inhibitors, kinetic and molecular docking studies. RSC Adv 2023; 13:24988-25001. [PMID: 37614781 PMCID: PMC10442672 DOI: 10.1039/d3ra05330j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 08/15/2023] [Indexed: 08/25/2023] Open
Abstract
A series of ten novel compounds were synthesized by incorporating a 1,3 thiazole core into amantadine and their structures were validated using different analytical and spectral methods such as FTIR, EI-MS, 1H NMR, and 13C NMR. The antibacterial and enzyme inhibitory properties of these newly synthesized compounds were evaluated. Remarkably, the compounds exhibited significant antibacterial activity against Escherichia coli and Bacillus subtilis. Additionally, the in vitro inhibitory activities of the synthesized compounds, against α-amylase, α-glucosidase, and urease were investigated. Among the tested compounds, compound 6d demonstrated potent and selective inhibition of α-amylase IC50 = 97.37 ± 1.52 μM, while acarbose was used as positive control and exhibited IC50 = 5.17 ± 0.25 μM. Compound 6d and 6e exhibited prominent inhibition against α-glucosidase IC50 = 38.73 ± 0.80 μM and 41.63 ± 0.26 μM respectively. Furthermore, compound 6d inhibited urease with exceptional efficacy IC50 = 32.76 μM, while positive control thiourea showed more prominent activity having IC50 = 1.334 μM. Molecular docking studies disclosed the binding mechanism and affinity of these new inhibitors within the binding sites of various amino acids. To investigate the association between molecular structural characteristics and inhibitory actions of synthesized derivatives, preliminary structure-activity relationship (SAR) studies were performed. These findings indicated that compounds 6a, 6c, 6d and 6e are potential candidates for hit-to-lead follow-up in the drug-discovery process for treating diabetes and hyperglycemia.
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Affiliation(s)
- Fatima Tuz Zahra
- Department of Chemistry, Quaid-i-Azam University 45320 Islamabad Pakistan +92-51-9064-2241 +92-51-9064-2128
| | - Aamer Saeed
- Department of Chemistry, Quaid-i-Azam University 45320 Islamabad Pakistan +92-51-9064-2241 +92-51-9064-2128
| | - Atteeque Ahmed
- Department of Chemistry, Quaid-i-Azam University 45320 Islamabad Pakistan +92-51-9064-2241 +92-51-9064-2128
| | - Hammad Ismail
- Department of Biochemistry and Biotechnology, University of Gujrat Gujrat 50700 Pakistan
| | - Muhammad Umar Ijaz
- Department of Zoology, Wildlife and Fisheries, University of Agriculture Faisalabad 38040 Pakistan
| | - Fernando Albericio
- Peptides Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal Westville Durban 4000 South Africa
- CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Department of Organic Chemistry, University of Barcelona 08028 Barcelona Spain
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13
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Klas K, Strzebonska K, Waligora M. Ethical challenges of clinical trials with a repurposed drug in outbreaks. MEDICINE, HEALTH CARE, AND PHILOSOPHY 2023; 26:233-241. [PMID: 36881334 PMCID: PMC9989564 DOI: 10.1007/s11019-023-10140-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/28/2023] [Indexed: 05/13/2023]
Abstract
Drug repurposing is a strategy of identifying new potential uses for already existing drugs. Many researchers adopted this method to identify treatment or prevention during the COVID-19 pandemic. However, despite the considerable number of repurposed drugs that were evaluated, only some of them were labeled for new indications. In this article, we present the case of amantadine, a drug commonly used in neurology that attracted new attention during the COVID-19 outbreak. This example illustrates some of the ethical challenges associated with the launch of clinical trials to evaluate already approved drugs. In our discussion, we follow the ethics framework for prioritization of COVID-19 clinical trials proposed by Michelle N Meyer and colleagues (2021). We focus on four criteria: social value, scientific validity, feasibility, and consolidation/collaboration. We claim that launching amantadine trials was ethically justified. Although the scientific value was anticipated to be low, unusually, the social value was expected to be high. This was because of significant social interest in the drug. In our view, this strongly supports the need for evidence to justify why the drug should not be prescribed or privately accessed by interested parties. Otherwise, a lack of evidence-based argument could enhance its uncontrolled use. With this paper, we join the discussion on the lessons learned from the pandemic. Our findings will help to improve future efforts to decide on the launch of clinical trials on approved drugs when dealing with the widespread off-label use of the drug.
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Affiliation(s)
- Katarzyna Klas
- Research Ethics in Medicine Study Group (REMEDY), Faculty of Health Sciences, Jagiellonian University Medical College, Michalowskiego 12, 31-126, Krakow, PL, Poland
| | - Karolina Strzebonska
- Research Ethics in Medicine Study Group (REMEDY), Faculty of Health Sciences, Jagiellonian University Medical College, Michalowskiego 12, 31-126, Krakow, PL, Poland
| | - Marcin Waligora
- Research Ethics in Medicine Study Group (REMEDY), Faculty of Health Sciences, Jagiellonian University Medical College, Michalowskiego 12, 31-126, Krakow, PL, Poland.
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14
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Gupta Y, Savytskyi OV, Coban M, Venugopal A, Pleqi V, Weber CA, Chitale R, Durvasula R, Hopkins C, Kempaiah P, Caulfield TR. Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics. Mol Aspects Med 2023; 91:101151. [PMID: 36371228 PMCID: PMC9613808 DOI: 10.1016/j.mam.2022.101151] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
Abstract
With more than 5 million fatalities and close to 300 million reported cases, COVID-19 is the first documented pandemic due to a coronavirus that continues to be a major health challenge. Despite being rapid, uncontrollable, and highly infectious in its spread, it also created incentives for technology development and redefined public health needs and research agendas to fast-track innovations to be translated. Breakthroughs in computational biology peaked during the pandemic with renewed attention to making all cutting-edge technology deliver agents to combat the disease. The demand to develop effective treatments yielded surprising collaborations from previously segregated fields of science and technology. The long-standing pharmaceutical industry's aversion to repurposing existing drugs due to a lack of exponential financial gain was overrun by the health crisis and pressures created by front-line researchers and providers. Effective vaccine development even at an unprecedented pace took more than a year to develop and commence trials. Now the emergence of variants and waning protections during the booster shots is resulting in breakthrough infections that continue to strain health care systems. As of now, every protein of SARS-CoV-2 has been structurally characterized and related host pathways have been extensively mapped out. The research community has addressed the druggability of a multitude of possible targets. This has been made possible due to existing technology for virtual computer-assisted drug development as well as new tools and technologies such as artificial intelligence to deliver new leads. Here in this article, we are discussing advances in the drug discovery field related to target-based drug discovery and exploring the implications of known target-specific agents on COVID-19 therapeutic management. The current scenario calls for more personalized medicine efforts and stratifying patient populations early on for their need for different combinations of prognosis-specific therapeutics. We intend to highlight target hotspots and their potential agents, with the ultimate goal of using rational design of new therapeutics to not only end this pandemic but also uncover a generalizable platform for use in future pandemics.
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Affiliation(s)
- Yash Gupta
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | - Oleksandr V Savytskyi
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; In Vivo Biosystems, Eugene, OR, USA
| | - Matt Coban
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | | | - Vasili Pleqi
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | - Caleb A Weber
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Rohit Chitale
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA; The Council on Strategic Risks, 1025 Connecticut Ave NW, Washington, DC, USA
| | - Ravi Durvasula
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | | | - Prakasha Kempaiah
- Department of Medicine, Infectious Diseases, Mayo Clinic, Jacksonville, FL, USA
| | - Thomas R Caulfield
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of QHS Computational Biology, Mayo Clinic, Jacksonville, FL, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA.
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15
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Iacono S, Schirò G, Davì C, Mastrilli S, Abbott M, Guajana F, Arnao V, Aridon P, Ragonese P, Gagliardo C, Colomba C, Scichilone N, D’Amelio M. COVID-19 and neurological disorders: what might connect Parkinson's disease to SARS-CoV-2 infection. Front Neurol 2023; 14:1172416. [PMID: 37273689 PMCID: PMC10232873 DOI: 10.3389/fneur.2023.1172416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/28/2023] [Indexed: 06/06/2023] Open
Abstract
SARS-CoV-2 infection leading to Coronavirus disease 19 (COVID-19) rapidly became a worldwide health emergency due to its elevated infecting capacity, morbidity, and mortality. Parkinson’s disease (PD) is the second most common neurodegenerative disorder and, nowadays the relationship between SARS-CoV-2 outbreak and PD reached a great interest. Apparently independent one from the other, both diseases share some pathogenetic and clinical features. The relationship between SARS-CoV-2 infection and PD is complex and it depends on the direction of the association that is which of the two diseases comes first. Some evidence suggests that SARS-CoV-2 infection might be a possible risk factor for PD wherein the exposure to SARS-CoV-2 increase the risk for PD. This perspective comes out from the increasing cases of parkinsonism following COVID-19 and also from the anatomical structures affected in both COVID-19 and early PD such as olfactory bulb and gastrointestinal tract resulting in the same symptoms such as hyposmia and constipation. Furthermore, there are many reported cases of patients who developed hypokinetic extrapyramidal syndrome following SARS-CoV-2 infection although these would resemble a post-encephalitic conditions and there are to date relevant data to support the hypothesis that SARS-CoV-2 infection is a risk factor for the development of PD. Future large, longitudinal and population-based studies are needed to better assess whether the risk of developing PD after COVID-19 exists given the short time span from the starting of pandemic. Indeed, this brief time-window does not allow the precise estimation of the incidence and prevalence of PD after pandemic when compared with pre-pandemic era. If the association between SARS-CoV-2 infection and PD pathogenesis is actually putative, on the other hand, vulnerable PD patients may have a greater risk to develop COVID-19 being also more prone to develop a more aggressive disease course. Furthermore, PD patients with PD showed a worsening of motor and non-motor symptoms during COVID-19 outbreak due to both infection and social restriction. As well, the worries related to the risk of being infected should not be neglected. Here we summarize the current knowledge emerging about the epidemiological, pathogenetic and clinical relationship between SARS-CoV-2 infection and PD.
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Affiliation(s)
- Salvatore Iacono
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Giuseppe Schirò
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Chiara Davì
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Sergio Mastrilli
- Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone di Palermo, Palermo, Italy
| | - Michelle Abbott
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Fabrizio Guajana
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Valentina Arnao
- UO Neurologia e Stroke Unit, Azienda di Rilievo Nazionale ad Alta Specializzazione, Ospedali Civico Di Cristina Benfratelli, Palermo, Italy
| | - Paolo Aridon
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Paolo Ragonese
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Cesare Gagliardo
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Claudia Colomba
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Nicola Scichilone
- Division of Respiratory Diseases, Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Marco D’Amelio
- Department of Biomedicine, Neuroscience, and Advanced Diagnostics, University of Palermo, Palermo, Italy
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Wu L, Shen J, Jiang Y, Shen X, Wang P, Nie X, Kang W, Liu J, Chen W. Clinical characteristics and outcome of COVID-19 patients with Parkinson's disease: a hospital-based case-control study in Shanghai, China. Front Aging Neurosci 2023; 15:1138418. [PMID: 37213541 PMCID: PMC10196628 DOI: 10.3389/fnagi.2023.1138418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 04/19/2023] [Indexed: 05/23/2023] Open
Abstract
Background Clinical manifestations of Parkinson's disease (PD) after Corona Virus Disease 2019 (COVID-19) infection are poorly investigated. Objective We aimed to explore the clinical features and outcomes of hospitalized PD patients with COVID-19. Methods A total of 48 PD patients and 96 age-and sex-matched non-PD patients were included. Demographics, clinical characteristics and outcomes were compared between two groups. Results PD patients with COVID-19 were elderly (76.69 ± 9.21 years) with advanced stage (H-Y stage 3-5 as 65.3%). They had less clinical symptoms (nasal obstruction, etc.), more proportions of severe/critical COVID-19 clinical classification (22.9 vs. 1.0%, p < 0.001), receiving oxygen (29.2 vs. 11.5%, p = 0.011), antibiotics (39.6 vs. 21.9%, p = 0.031) therapies, as well as longer hospitalization duration (11.39 vs. 8.32, p = 0.001) and higher mortality (8.3% vs. 1.0%, p = 0.001) relative to those without PD. Laboratory results showed that the PD group had higher white blood cell counts (6.29 vs. 5.16*109, p = 0.001), neutrophil-to-lymphocyte ratio (3.14 vs. 2.11, p < 0.001) and C-reactive protein level (12.34 vs. 3.19, p < 0.001). Conclusion PD patients with COVID-19 have insidious clinical manifestation, elevated proinflammatory markers and are prone to the development of severe/critical condition, contributing to a relatively poor prognosis. Early identification and active treatment of COVID-19 are pivotal to advanced PD patients during the pandemic.
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Affiliation(s)
- Li Wu
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Shen
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhan Jiang
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolei Shen
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ping Wang
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Nie
- Biostatistics Office of Clinical Research Unit, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenyan Kang
- Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Shanghai, Hainan, China
| | - Jianren Liu
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Chen
- Department of Neurology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Efficacy of oral amantadine among patients hospitalised with COVID-19: A randomised, double-blind, placebo-controlled, multicentre study. Respir Med 2023; 212:107198. [PMID: 36931576 PMCID: PMC10015090 DOI: 10.1016/j.rmed.2023.107198] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 03/17/2023]
Abstract
BACKGROUND Amantadine has been proposed as a treatment for COVID-19 because it shows anti-SARS-CoV-2 activity in vitro. However, to date, no controlled study has assessed the safety and efficacy of amantadine in COVID-19. RESEARCH QUESTION Whether amantadine is effective and safe among patients with different COVID-19 severity classifications. STUDY DESIGN and Methods: This was multi-centre, randomised, placebo-controlled study.Patients with oxygen saturation ≤94% and no need for high-flow oxygen or ventilatory support were randomly allocated to receive oral amantadine or placebo (1:1) for 10 days in addition to standard care. The primary endpoint was time to recovery assessed over 28 days since randomisation, defined as discharge from hospital or no need for supplemental oxygen. RESULTS The study was terminated early due to a lack of efficacy after an interim analysis. Final data from 95 patients who received amantadine (mean age, 60.2 years; 65% male; 66% with comorbidities) and 91 patients who received placebo (mean age, 55.8 years; 60% male; 68% with comorbidities) were obtained. The median (95% CI) time to recovery was 10 days both in the amantadine (9-11) and placebo arms (8-11; subhazard ratio = 0.94 [95%CI 0.7-1.3]). The percentage of deaths and percentage of patients who required intensive care at 14 and 28 days did not significantly differ between the amantadine and placebo groups. INTERPRETATION Adding amantadine to standard care in patients hospitalised with COVID-19 did not increase the likelihood of recovery. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov; No.: NCT04952519; www. CLINICALTRIALS gov.
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18
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Butterworth RF. Adamantanes for the treatment of neurodegenerative diseases in the presence of SARS-CoV-2. Front Neurosci 2023; 17:1128157. [PMID: 36968489 PMCID: PMC10031118 DOI: 10.3389/fnins.2023.1128157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 02/14/2023] [Indexed: 03/29/2023] Open
Abstract
Advent of the acute respiratory coronavirus SARS-CoV-2 has resulted in the search for novel antiviral agents and in the repurposing of existing agents with demonstrated efficacy against other known coronaviruses in the search for an agent with antiviral activity for use during the COVID-19 pandemic. Adamantanes including amantadine, rimantadine, and memantine have well-established benefit in the treatment of neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD) and fatigue related to Multiple sclerosis (MS) all of which are known comorbidities related to COVID-19 Moreover, results of basic pharmacological studies both in vitro and in vivo reveal that amantadine has the potential to inhibit SARS-CoV-2 via down-regulation of host-cell proteases resulting in impaired viral genome release into the host cell and via amantadine's property as an NMDA receptor antagonist resulting in the prevention of the acute lung injury and respiratory distress that is characteristic of COVID-19. Cases suggestive of COVID-19 prophylaxis have been reported in patients with PD or MS or severe cognitive impairment treated in all cases for several months with an adamantane [amantadine or memantine] who were subsequently infected with SARS-CoV-2 confirmed by RT-PCR, and, in all cases, no signs of infectious disease were encountered. Amantadine is effective for the treatment of fatigue in MS and for the neurological complications of Traumatic Brain Injury (TBI).
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Nadwa EH, Al-Kuraishy HM, Al-Gareeb AI, Elekhnawy E, Albogami SM, Alorabi M, Batiha GES, De Waard M. Cholinergic dysfunction in COVID-19: frantic search and hoping for the best. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:453-468. [PMID: 36460816 PMCID: PMC9735034 DOI: 10.1007/s00210-022-02346-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/18/2022] [Indexed: 12/05/2022]
Abstract
A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.
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Affiliation(s)
- Eman Hassan Nadwa
- Department of Pharmacology and Therapeutics, College of Medicine, Jouf University, Sakakah, 72345 Saudi Arabia
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Giza, 12613 Egypt
| | - Hayder M. Al-Kuraishy
- Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, 14132 Iraq
| | - Ali I. Al-Gareeb
- Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriyah University, Baghdad, 14132 Iraq
| | - Engy Elekhnawy
- Microbiology and Immunology Department, Faculty of Pharmacy, Tanta University, Tanta, 31527 Egypt
| | - Sarah M. Albogami
- Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif, 21944 Saudi Arabia
| | - Mohammed Alorabi
- Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif, 21944 Saudi Arabia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511 Al Beheira Egypt
| | - Michel De Waard
- Smartox Biotechnology, 6 Rue Des Platanes, 38120 Saint-Egrève, France
- L’Institut du Thorax, INSERM, CNRS, UNIV NANTES, 44007 Nantes, France
- LabEx “Ion Channels, Science & Therapeutics”, Université de Nice Sophia-Antipolis, 06560 Valbonne, France
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20
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Müller T, Riederer P, Kuhn W. Aminoadamantanes: from treatment of Parkinson's and Alzheimer's disease to symptom amelioration of long COVID-19 syndrome? Expert Rev Clin Pharmacol 2023; 16:101-107. [PMID: 36726198 DOI: 10.1080/17512433.2023.2176301] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
INTRODUCTION The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists. AREAS COVERED The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinson's disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimer's disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca2+ ions as the main responsible components of neuronal excitotoxicity. This causes neuronal dying and associated functional deficits. EXPERT OPINION We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes.
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Affiliation(s)
- Thomas Müller
- Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Gartenstr. 1, 13088, Berlin, Germany
| | - Peter Riederer
- Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Füchsleinstrasse 15, 97080, Würzburg, Germany
| | - Wilfried Kuhn
- Department of Neurology, Leopoldina Hospital Schweinfurt, Gustav Adolf Str. 8, 97422, Schweinfurt, Germany
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Huang P, Zhang LY, Tan YY, Chen SD. Links between COVID-19 and Parkinson's disease/Alzheimer's disease: reciprocal impacts, medical care strategies and underlying mechanisms. Transl Neurodegener 2023; 12:5. [PMID: 36717892 PMCID: PMC9885419 DOI: 10.1186/s40035-023-00337-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest. However, there are still many issues of concern to be clarified. Therefore, we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinson's disease (PD) and Alzheimer's disease (AD). We summarize the impact of COVID-19 infection on symptom severity, disease progression, and mortality rate of PD and AD, and discuss whether COVID-19 infection could trigger PD and AD. In addition, the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included. In order to achieve better management of PD and AD patients, modifications of care strategies, specific drug therapies, and vaccines during the pandemic are also listed. At last, mechanisms underlying the link of COVID-19 with PD and AD are reviewed.
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Affiliation(s)
- Pei Huang
- grid.16821.3c0000 0004 0368 8293Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
| | - Lin-Yuan Zhang
- grid.412478.c0000 0004 1760 4628Department of Neurology, Shanghai General Hospital, Shanghai, 200080 China
| | - Yu-Yan Tan
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Sheng-Di Chen
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. .,Lab for Translational Research of Neurodegenerative Diseases, Shanghai Institute for Advanced Immunochemical Studies (SIAIS), Shanghai Tech University, Shanghai, 201210, China.
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22
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Yuan Y, Jiao B, Qu L, Yang D, Liu R. The development of COVID-19 treatment. Front Immunol 2023; 14:1125246. [PMID: 36776881 PMCID: PMC9909293 DOI: 10.3389/fimmu.2023.1125246] [Citation(s) in RCA: 126] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 01/03/2023] [Indexed: 01/27/2023] Open
Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic named coronavirus disease 2019 (COVID-19) that has become the greatest worldwide public health threat of this century. Recent studies have unraveled numerous mysteries of SARS-CoV-2 pathogenesis and thus largely improved the studies of COVID-19 vaccines and therapeutic strategies. However, important questions remain regarding its therapy. In this review, the recent research advances on COVID-19 mechanism are quickly summarized. We mainly discuss current therapy strategies for COVID-19, with an emphasis on antiviral agents, neutralizing antibody therapies, Janus kinase inhibitors, and steroids. When necessary, specific mechanisms and the history of therapy are present, and representative strategies are described in detail. Finally, we discuss key outstanding questions regarding future directions of the development of COVID-19 treatment.
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Affiliation(s)
- Yongliang Yuan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Baihai Jiao
- Division of Nephrology, Department of Medicine, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Lili Qu
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
| | - Duomeng Yang
- Department of Immunology, School of Medicine, University of Connecticut Health Center, Farmington, CT, United States,*Correspondence: Ruijuan Liu, ; Duomeng Yang,
| | - Ruijuan Liu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,*Correspondence: Ruijuan Liu, ; Duomeng Yang,
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Nesterowicz M, Żendzian-Piotrowska M, Ładny JR, Zalewska A, Maciejczyk M. Antiglycoxidative properties of amantadine – a systematic review and comprehensive in vitro study. J Enzyme Inhib Med Chem 2023; 38:138-155. [PMID: 36325591 PMCID: PMC9639497 DOI: 10.1080/14756366.2022.2137161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
An important drug used in the treatment of Parkinson’s disease is amantadine. We are the first to perform a comprehensive study based on various glycation and oxidation factors, determining the impact of amantadine on protein glycoxidation. Sugars (glucose, fructose, galactose) and aldehydes (glyoxal, methylglyoxal) were used as glycation agents, and chloramine T was used as an oxidant. Glycoxidation biomarkers in albumin treated with amantadine were generally not different from the control group (glycation/oxidation factors), indicating that the drug did not affect oxidation and glycation processes. Molecular docking analysis did not reveal strong binding sites of amantadine on the bovine serum albumin structure. Although amantadine poorly scavenged hydroxyl radical and hydrogen peroxide, it had significantly lower antioxidant and antiglycation effect than all protein oxidation and glycation inhibitors. In some cases, amantadine even demonstrated glycoxidant, proglycation, and prooxidant properties. In summary, amantadine exhibited weak antioxidant properties and a lack of antiglycation activity.
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Affiliation(s)
- Miłosz Nesterowicz
- Students’ Scientific Club “Biochemistry of Civilization Diseases” at the Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Białystok, Poland
| | | | - Jerzy Robert Ładny
- 1st Department of General Surgery and Endocrinology, Medical University of Bialystok, Białystok, Poland
| | - Anna Zalewska
- Independent Laboratory of Experimental Dentistry, Medical University of Bialystok, Białystok, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Białystok, Poland
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Przytuła F, Kasprzak J, Dulski J, Koziorowski D, Kwaśniak-Butowska M, Sołtan W, Roszmann A, Śmiłowska K, Schinwelski M, Sławek J. Morbidity and severity of COVID-19 in patients with Parkinson's disease treated with amantadine - A multicenter, retrospective, observational study. Parkinsonism Relat Disord 2023; 106:105238. [PMID: 36509028 PMCID: PMC9724557 DOI: 10.1016/j.parkreldis.2022.105238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/19/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND After more than 2 years of the pandemic, effective treatment for COVID-19 is still under research. In recent months, publications hypothesized amantadine's potential beneficial effect on SARS-CoV-2 infection. OBJECTIVE To compare the groups of Parkinson's Disease (PD) patients who were administered amantadine chronically and those who did not take this medication in the context of the incidence and severity of COVID-19 infection. METHODS An observational, retrospective, multicenter cohort study was conducted among consecutive patients with idiopathic PD. The structured questionnaires were completed during the patient's follow-up visits at the Outpatient Clinic or during hospitalization. The questionnaire included the following informations: patient's age, duration of PD, Hoehn-Yahr (H-Y) stage, comorbidities, medications, COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR) swab test for SARS-CoV-2 with specified symptoms and their severity (home or hospital treatment). The vaccination status was verified as well. RESULTS Five hundred fifty-two (n = 552) patients participated in the study - 329 men (60%). The mean H-Y stage was 2.44 (range: 1-4) and the mean duration of PD was 9.6 years (range: 1-34). One hundred four subjects (19%) had confirmed COVID-19 infection. Subjects over 50 years of age had a significantly lower incidence of COVID-19 (17% vs 38%, p = 0.0001) with difference also in mean H-Y stage (2.27 vs 2.49; p = 0.011) and disease duration (8.4 vs 9.9 years, p = 0.007). There were no differences between patients with and without co-morbidities. In the whole analyzed group 219 (40%) subjects were treated with amantadine. Comparing COVID-19 positive and negative patients, amantadine was used by 48/104 (46%) and 171/448 (38%) respectively. 22% of patients on amantadine vs. 17% of patients without amantadine developed COVID-19. These differences were not significant. There were no differences in morbidity and severity of COVID-19 between amantadine users and non-users as well. CONCLUSIONS COVID-19 was less common in older (>50) with longer duration and more advanced patients. Amantadine did not affect the risk of developing COVID-19 or the severity of infection.
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Affiliation(s)
- Filip Przytuła
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland.
| | - Jakub Kasprzak
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland
| | - Jarosław Dulski
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland; Department of Neurological-Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, Poland; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA
| | - Dariusz Koziorowski
- Neurology Dpt, Faculty of Health Sciences, Medical University of Warsaw, Poland and Bródno Hospital, Warsaw, Poland
| | - Magdalena Kwaśniak-Butowska
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland; Department of Neurological-Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, Poland
| | - Witold Sołtan
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland
| | - Anna Roszmann
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland; Department of Neurological-Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, Poland
| | | | | | - Jarosław Sławek
- Neurology&Stroke Dpt, St. Adalbert Hospital, Gdańsk, Poland; Department of Neurological-Psychiatric Nursing, Faculty of Health Sciences, Medical University of Gdańsk, Poland.
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25
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Ning X, Qiu J. A semi-quantitative multi-range lateral flow immunoassay for amantadine residues in livestock and poultry products. FOOD AGR IMMUNOL 2022. [DOI: 10.1080/09540105.2022.2137472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Xiangxue Ning
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agri-Food Quality and Safety, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of China
- Graduate School of Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of China
| | - Jing Qiu
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agri-Food Quality and Safety, Ministry of Agriculture and Rural Affairs, Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of China
- Graduate School of Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of China
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26
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Zalyalova ZA, Munasipova SE, Khasanova DM, Ilyina GR, Khayatova ZG, Bagdanova NI. A “new” role of amantadines in COVID-19 in patients with Parkinson’s disease: results of own comparative study. NEUROLOGY, NEUROPSYCHIATRY, PSYCHOSOMATICS 2022. [DOI: 10.14412/2074-2711-2022-6-40-48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Z. A. Zalyalova
- Kazan State Medical University, Ministry of Health of Russia; Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy, Ministry of Health of the Republic of Tatarstan; Hospital for War Veterans; Clinical Hospital “Railway Medicine“
| | - S. E. Munasipova
- Kazan State Medical University, Ministry of Health of Russia; Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy, Ministry of Health of the Republic of Tatarstan; Hospital for War Veterans
| | - D. M. Khasanova
- Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy, Ministry of Health of the Republic of Tatarstan; Hospital for War Veterans
| | - G. R. Ilyina
- Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy, Ministry of Health of the Republic of Tatarstan; Hospital for War Veterans
| | | | - N. I. Bagdanova
- Republican Clinical Diagnostic Center for Extrapyramidal Pathology and Botulinum Therapy, Ministry of Health of the Republic of Tatarstan; Hospital for War Veterans
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27
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Tatar D, Świerzy K, Błachut M, Badura Brzoza K. Psychotic Disorders in the Course of SARS-CoV-2 Infection or Uncomplicated Amantadine Treatment?-Case Report. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:15768. [PMID: 36497843 PMCID: PMC9735925 DOI: 10.3390/ijerph192315768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/25/2022] [Accepted: 11/21/2022] [Indexed: 06/17/2023]
Abstract
The mental health impact of SARS-CoV-2 infection is currently the subject of intense research. Mental disorders in the course of coronavirus infection are non-specific. They most often have a sudden onset and short-term course and resolve spontaneously or after the administration of low doses of antipsychotic drugs. At the same time, attempts have been made to develop recommendations for COVID-19 therapy. Single reports suggest the effectiveness of amantadine in the treatment. The mechanism of action of the drug in this case is not known; it is expected that amantadine, by reducing the expression of the cathepsin L gene, may interfere with SARS-CoV-2 replication. In addition, this drug stimulates dopaminergic transmission, which may result in numerous side effects, often of a neuropsychological nature, the most common of which are visual hallucinations. Therefore, it is extremely difficult to unequivocally diagnose the cause of mental disorders among patients with SARS-CoV-2 infection who took amatatide for off-label treatment. A clear assessment of whether the psychological symptoms in this group of patients are the primary or secondary clinical manifestation of the infection or a complication of amantadine treatment is difficult. In this context, we attempted to describe a case of a patient with psychotic symptoms who was confirmed with SARS-CoV-2 infection and treated with amantadine.
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Affiliation(s)
- Dominika Tatar
- Clinical Department of Psychiatry, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
| | | | | | - Karina Badura Brzoza
- Clinical Department of Psychiatry, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland
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28
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Lim SY, Guo Z, Liu P, McKay LGA, Storm N, Griffiths A, Qu MD, Finberg RW, Somasundaran M, Wang JP. Anti-SARS-CoV-2 Activity of Adamantanes In Vitro and in Animal Models of Infection. COVID 2022; 2:1551-1563. [PMID: 37274537 PMCID: PMC10238102 DOI: 10.3390/covid2110111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Coronavirus disease 2019 (COVID-19) has had devastating effects worldwide, with particularly high morbidity and mortality in outbreaks on residential care facilities. Amantadine, originally licensed as an antiviral agent for therapy and prophylaxis against influenza A virus, has beneficial effects on patients with Parkinson's disease and is used for treatment of Parkinson's disease, multiple sclerosis, acquired brain injury, and various other neurological disorders. Recent observational data suggest an inverse relationship between the use of amantadine and COVID-19. Adamantanes, including amantadine and rimantadine, are reported to have in vitro activity against severe acute respiratory syndrome coronavirus (SARS-CoV) and, more recently, SARS-CoV-2. We hypothesized that adamantanes have antiviral activity against SARS-CoV-2, including variant strains. To assess the activity of adamantanes against SARS-CoV-2, we used in vitro and in vivo models of infection. We established that amantadine, rimantadine, and tromantadine inhibit the growth of SARS-CoV-2 in vitro in cultured human epithelial cells. While neither rimantadine nor amantadine reduces lung viral titers in mice infected with mouse-adapted SARS-CoV-2, rimantadine significantly reduces viral titers in the lungs in golden Syrian hamsters infected with SARS-CoV-2. In summary, rimantadine has antiviral activity against SARS-CoV-2 in human alveolar epithelial cells and in the hamster model of SARS-CoV-2 lung infection. The evaluation of amantadine or rimantadine in human randomized controlled trials can definitively address applications for the treatment or prevention of COVID-19.
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Affiliation(s)
- Sun-Young Lim
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Zhiru Guo
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Ping Liu
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Lindsay G. A. McKay
- Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02115, USA
| | - Nadia Storm
- Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02115, USA
| | - Anthony Griffiths
- Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02115, USA
| | - Ming Da Qu
- Division of Infectious Disease & Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Robert W. Finberg
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Mohan Somasundaran
- Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
| | - Jennifer P. Wang
- Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
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Kaliappan A, Gaur A, Sakthivadivel V, Balan Y, Tadi LJ, Sundaramurthy R. COVID-19 and Dementia; Hard to Forget Yet Haunting Forgetfulness! Ann Indian Acad Neurol 2022; 25:832-840. [PMID: 36561000 PMCID: PMC9764909 DOI: 10.4103/aian.aian_42_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/22/2022] [Accepted: 04/04/2022] [Indexed: 01/08/2023] Open
Abstract
The current pandemic has affected almost everyone worldwide. Although the majority of people survive the illness, bad cognitive repercussions might last a long time, resulting in a lower quality of life and disability, particularly in severe cases. We tried to understand and bring together the various possible mechanisms leading to dementia in COVID-19. The link between COVID-19 and dementia will help public health workers plan and allocate resources to provide better care for a community suffering from sickness and improve quality of life. A conceptual framework for care of infected people in the older age group and care of dementia people is proposed.
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Affiliation(s)
- Ariyanachi Kaliappan
- Department of Anatomy, All India Institute of Medical Sciences, Bibinagar, Hyderabad, Telangana, India
| | - Archana Gaur
- Department of Physiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, Telangana, India
| | - Varatharajan Sakthivadivel
- Department of General Medicine, All India Institute of Medical Sciences, Bibinagar, Hyderabad, Telangana, India
| | - Yuvaraj Balan
- Department of Biochemistry, All India Institute of Medical Sciences, Bibinagar, Hyderabad, Telangana, India
| | - Lakshmi Jyothi Tadi
- Department of Microbiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, Telangana, India
| | - Raja Sundaramurthy
- Department of Microbiology, All India Institute of Medical Sciences, Bibinagar, Hyderabad, Telangana, India
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Dopamine Reduces SARS-CoV-2 Replication In Vitro through Downregulation of D2 Receptors and Upregulation of Type-I Interferons. Cells 2022; 11:cells11101691. [PMID: 35626728 PMCID: PMC9139638 DOI: 10.3390/cells11101691] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/13/2022] [Accepted: 05/18/2022] [Indexed: 02/06/2023] Open
Abstract
Recent evidence suggests that SARS-CoV-2 hinders immune responses via dopamine (DA)-related mechanisms. Nonetheless, studies addressing the specific role of DA in the frame of SARS-CoV-2 infection are still missing. In the present study, we investigate the role of DA in SARS-CoV-2 replication along with potential links with innate immune pathways in CaLu-3 human epithelial lung cells. We document here for the first time that, besides DA synthetic pathways, SARS-CoV-2 alters the expression of D1 and D2 DA receptors (D1DR, D2DR), while DA administration reduces viral replication. Such an effect occurs at non-toxic, micromolar-range DA doses, which are known to induce receptor desensitization and downregulation. Indeed, the antiviral effects of DA were associated with a robust downregulation of D2DRs both at mRNA and protein levels, while the amount of D1DRs was not significantly affected. While halting SARS-CoV-2 replication, DA, similar to the D2DR agonist quinpirole, upregulates the expression of ISGs and Type-I IFNs, which goes along with the downregulation of various pro-inflammatory mediators. In turn, administration of Type-I IFNs, while dramatically reducing SARS-CoV-2 replication, converges in downregulating D2DRs expression. Besides configuring the CaLu-3 cell line as a suitable model to study SARS-CoV-2-induced alterations at the level of the DA system in the periphery, our findings disclose a previously unappreciated correlation between DA pathways and Type-I IFN response, which may be disrupted by SARS-CoV-2 for host cell invasion and replication.
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Rejdak K, Fiedor P, Bonek R, Goch A, Gala-Błądzińska A, Chełstowski W, Łukasiak J, Kiciak S, Dąbrowski P, Dec M, Król ZJ, Papuć E, Zasybska A, Segiet A, Grieb P. The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design. Contemp Clin Trials 2022; 116:106755. [PMID: 35390511 PMCID: PMC8978450 DOI: 10.1016/j.cct.2022.106755] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 03/23/2022] [Accepted: 04/01/2022] [Indexed: 11/24/2022]
Abstract
Background COVID-19, a disease caused by infection with the SARS-CoV-2 virus, is asymptomatic or mildly symptomatic in most cases. Some patients, usually burdened with risk factors develop acute respiratory failure and other organ dysfunction. In such cases, the mortality rate is very high despite the use of intensive therapy. Amantadine has complex activity including antiviral, antiinflammatory and dopaminergic effects. This clinical trial will assess the efficacy and safety of amantadine in the prevention of COVID-19 progression toward acute respiratory failure and neurological complications. Methods and results The trial will enroll 200 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as hospitalized or ambulatory subjects for early treatment of illness. The recruitment will take place in 8 centers covering different regions of Poland. For 14 days they will be given either 200 mg of amantadine a day or placebo. Our hypothesis is a considerable reduction in the number of patients with progression toward respiratory insufficiency or neurological complications thanks to the treatment of amantadine. Conclusions Demonstrating the efficacy and safety of amantadine treatment in improving the clinical condition of patients diagnosed with COVID-19 is of great importance in combating the effects of the pandemic. It has potential to influence on the severity and course of neurological complications, which are very common and persist long after the infection as long-COVID syndrome. Clinical trial registration:www.clinicaltrials.gov identification no. NCT04854759; Eudra CT number: 2021–001144-98 (dated 27 February 2021).
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Affiliation(s)
- Konrad Rejdak
- Department of Neurology, Medical University of Lublin, Lublin, Poland.
| | - Piotr Fiedor
- Department of General and Transplantation Surgery, Medical University of Warsaw, Poland
| | - Robert Bonek
- Department of Neurology and Clinical Neuroimmunology, Regional Specialist Hospital, Grudziadz, Poland
| | - Aleksander Goch
- Department of Neurology and Clinical Neuroimmunology, Regional Specialist Hospital, Grudziadz, Poland
| | - Agnieszka Gala-Błądzińska
- Faculty of Medicine, University of Rzeszów, Rzeszów, Poland; St' Queen Jadwiga Clinical District Hospital No. 2, Rzeszów, Poland
| | | | | | - Sławomir Kiciak
- Independent Voivodeship Hospital "Jana Bożego" in Lublin, Lublin, Poland
| | - Piotr Dąbrowski
- Independent Voivodeship Hospital "Jana Bożego" in Lublin, Lublin, Poland
| | - Mateusz Dec
- SPZOZ Kalwaria Zebrzydowska, Kalwaria Zebrzydowska, Poland
| | - Zbigniew J Król
- Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
| | - Ewa Papuć
- Department of Neurology, Medical University of Lublin, Lublin, Poland
| | - Adriana Zasybska
- Department of Neurology, Medical University of Lublin, Lublin, Poland
| | - Agnieszka Segiet
- Chair and Department of Experimental and Clinical Physiology, Medical University of Warsaw, Poland
| | - Paweł Grieb
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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Rejdak K, Grieb P. Fluvoxamine and Amantadine: Central Nervous System Acting Drugs Repositioned for COVID-19 as Early Intervention. Curr Neuropharmacol 2022; 20:777-781. [PMID: 34325642 PMCID: PMC9878960 DOI: 10.2174/1570159x19666210729123734] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/23/2021] [Accepted: 07/09/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND As the World faces unprecedented pandemic caused by SARS-CoV-2 virus, repositioning of existing drugs to treatment of COVID-19 disease is urgently awaited, provided that high quality scientific evidence supporting safety and efficacy in this new indication is gathered. Efforts concerning drugs repositioning to COVID-19 were mostly focused on antiviral drugs, or drugs targeting the late phase of the disease. METHODS Based on published research, the pharmacological activities of fluvoxamine and amantadine, two well-known drugs widely used in clinical practice for psychiatric and neurological diseases, respectively, have been reviewed, with a focus on their potential therapeutic importance in the treatment of COVID-19. RESULTS Several preclinical and clinical reports were identified suggesting that these two drugs might exert protective effects in the early phases of COVID-19. CONCLUSION Preclinical and early clinical evidence are presented indicating that these drugs hold promise to prevent COVID-19 progression when administered early during the course of infection.
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Affiliation(s)
- Konrad Rejdak
- Department of Neurology, Medical University of Lublin, Lublin, Poland
| | - Paweł Grieb
- Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland,Address correspondence to this author at the Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego str., 02-106 Warsaw, Poland; Tel: (+48) 226086527; E-mail:
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Świerczyńska M, Mirowska-Guzel DM, Pindelska E. Antiviral Drugs in Influenza. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19053018. [PMID: 35270708 PMCID: PMC8910682 DOI: 10.3390/ijerph19053018] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 11/30/2022]
Abstract
Flu is a serious health, medical, and economic problem, but no therapy is yet available that has satisfactory results and reduces the occurrence of these problems. Nearly 20 years after the registration of the previous therapy, baloxavir marboxil, a drug with a new mechanism of action, recently appeared on the market. This is a promising step in the fight against the influenza virus. This article presents the possibilities of using all available antiviral drugs specific for influenza A and B. We compare all currently recommended anti-influenza medications, considering their mechanisms of action, administration, indications, target groups, effectiveness, and safety profiles. We demonstrate that baloxavir marboxil presents a similar safety and efficacy profile to those of drugs already used in the treatment of influenza. Further research on combination therapy is highly recommended and may have promising results.
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Affiliation(s)
- Magdalena Świerczyńska
- Centre for Preclinical Research and Technology CePT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland;
| | - Dagmara M. Mirowska-Guzel
- Centre for Preclinical Research and Technology CePT, Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland;
- Correspondence: ; Tel.: +48-22-116-6160; Fax: +48-22-116-6202
| | - Edyta Pindelska
- Department of Analytical Chemistry and Biomaterials, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1B, 02-093 Warsaw, Poland;
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Network-Based Approach to Repurpose Approved Drugs for COVID-19 by Integrating GWAS and Text Mining Data. Processes (Basel) 2022. [DOI: 10.3390/pr10020326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The coronavirus disease 19 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a rapidly increasing prevalence and has caused significant morbidity/mortality. Despite the availability of many vaccines that can offer widespread immunization, it is also important to reach effective treatment for COVID-19 patients. However, the development of novel drug therapeutics is usually a time-consuming and costly process, and therefore, repositioning drugs that were previously approved for other purposes could have a major impact on the fight against COVID-19. Here, we first identified lung-specific gene regulatory/interaction subnetworks (COVID-19-related genes modules) enriched for COVID-19-associated genes obtained from GWAS and text mining. We then screened the targets of 220 approved drugs from DrugBank, obtained their drug-induced gene expression profiles in the LINCS database, and constructed lung-specific drug-related gene modules. By applying an integrated network-based approach to quantify the interactions of the COVID-19-related gene modules and drug-related gene modules, we prioritized 13 approved drugs (e.g., alitretinoin, clocortolone, terazosin, doconexent, and pergolide) that could potentially be repurposed for the treatment of COVID-19. These findings provide important and timely insights into alternative therapeutic options that should be further explored as COVID-19 continues to spread.
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Drelich-Zbroja A, Cheda M, Kuczyńska M, Dąbrowska I, Kopyto E, Halczuk I. Parkinson's Disease in Light of the COVID-19 Pandemic. Brain Sci 2022; 12:143. [PMID: 35203906 PMCID: PMC8869942 DOI: 10.3390/brainsci12020143] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
In this review we attempt to collate the existing scientific evidence regarding the possible role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pathophysiology of Parkinson's disease (PD), as well as to investigate the impact of PD/parkinsonism on the clinical course of the viral infection itself. Since etiology of PD is not completely understood, various studies suggest different potential links between coronavirus disease 2019 (COVID-19) and PD. Suggested connections include, among others, similar prodromal symptoms, renin-angiotensin-aldosterone system involvement, or gut microbiome dysbiosis participation. Despite the initial assumptions that, as a mainly elderly population suffering from rigidity of respiratory muscles, impairment of cough reflex, and dyspnea, PD patients would be more susceptible to viral infection, and would experience a more aggressive course of COVID-19, the published scientific reports contain mutually exclusive data that require further investigation and meta-analysis.
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Affiliation(s)
- Anna Drelich-Zbroja
- Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-059 Lublin, Poland; (M.C.); (M.K.); (I.D.)
| | - Mateusz Cheda
- Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-059 Lublin, Poland; (M.C.); (M.K.); (I.D.)
| | - Maryla Kuczyńska
- Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-059 Lublin, Poland; (M.C.); (M.K.); (I.D.)
| | - Izabela Dąbrowska
- Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-059 Lublin, Poland; (M.C.); (M.K.); (I.D.)
| | - Ewa Kopyto
- Students’ Scientific Society at the Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-059 Lublin, Poland; (E.K.); (I.H.)
| | - Izabela Halczuk
- Students’ Scientific Society at the Department of Interventional Radiology and Neuroradiology, Medical University of Lublin, 20-059 Lublin, Poland; (E.K.); (I.H.)
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Bakhati B, Sibi VM, Mekala AP, Ronen JA, Mungara SS. Amantadine-Induced Cardiac Arrest in a Patient With COVID-19. Cureus 2022; 14:e21345. [PMID: 35186602 PMCID: PMC8850186 DOI: 10.7759/cureus.21345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2022] [Indexed: 11/05/2022] Open
Abstract
Amantadine, which is known for its antiviral activity, is presently used as therapy for Parkinson's disease. Adverse effects, such as cardiac arrhythmias, have been described in patients after ingestion of amantadine. Here, we present a patient who suffered a cardiac arrest following ingestion of a low dose of amantadine. A 71-year-old man was admitted to the emergency department for a witnessed cardiac arrest. He had developed an upper respiratory tract infection the preceding week and was prescribed 100 mg of amantadine. Within half an hour of taking the first dose, the patient collapsed. He was found to be in asystole by emergency medical services, and advanced cardiac life support protocols were initiated, including cardiopulmonary resuscitation and intubation for airway protection. However, he sustained multiple recurrences of cardiac arrest, and despite all resuscitation efforts, the patient expired.
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37
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Wen D, Xu J, Wu Z, Liu Y, Zhou Y, Li J, Wang S, Dong X, Saripan MI, Song H. The Effective Cognitive Assessment and Training Methods for COVID-19 Patients With Cognitive Impairment. Front Aging Neurosci 2022; 13:827273. [PMID: 35087399 PMCID: PMC8787269 DOI: 10.3389/fnagi.2021.827273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 12/16/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Dong Wen
- Brain Computer Intelligence and Intelligent Health Institution, Institute of Artificial Intelligence, University of Science and Technology Beijing, Beijing, China
| | - Jian Xu
- The Key Laboratory for Computer Virtual Technology and System Integration of Hebei Province, School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
| | - Zhonglin Wu
- The Key Laboratory for Computer Virtual Technology and System Integration of Hebei Province, School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
| | - Yijun Liu
- Department of Statistics, School of Science, Yanshan University, Qinhuangdao, China
| | - Yanhong Zhou
- Department of Computer Science and Technology, School of Mathematics and Information Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, China
- *Correspondence: Yanhong Zhou
| | - Jingjing Li
- The Key Laboratory for Computer Virtual Technology and System Integration of Hebei Province, School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
| | - Shaochang Wang
- The Key Laboratory for Computer Virtual Technology and System Integration of Hebei Province, School of Information Science and Engineering, Yanshan University, Qinhuangdao, China
| | - Xianlin Dong
- Department of Biomedical Engineering, Chengde Medical University, Chengde, China
| | - M. Iqbal Saripan
- Department of Computer and Communication Systems Engineering, Faculty of Engineering, Universiti Putra Malaysia, Serdang, Malaysia
| | - Haiqing Song
- Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
- Haiqing Song
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Perez-Lemus GR, Menéndez CA, Alvarado W, Byléhn F, de Pablo JJ. Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors. SCIENCE ADVANCES 2022; 8:eabj4526. [PMID: 34995115 PMCID: PMC8741187 DOI: 10.1126/sciadv.abj4526] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 11/17/2021] [Indexed: 05/31/2023]
Abstract
To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.
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Affiliation(s)
| | - Cintia A. Menéndez
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
- INQUISUR, Departamento de Química, Universidad Nacional del Sur (UNS)-CONICET, Avenida Alem 1253, 8000 Bahía Blanca, Argentina
| | - Walter Alvarado
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
- Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Fabian Byléhn
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
| | - Juan J. de Pablo
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, USA
- Argonne National Laboratory, 9700 Cass Ave, Lemont, IL 60439 USA
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Damiano RF, Guedes BF, de Rocca CC, de Pádua Serafim A, Castro LHM, Munhoz CD, Nitrini R, Filho GB, Miguel EC, Lucchetti G, Forlenza O. Cognitive decline following acute viral infections: literature review and projections for post-COVID-19. Eur Arch Psychiatry Clin Neurosci 2022; 272:139-154. [PMID: 34173049 PMCID: PMC8231753 DOI: 10.1007/s00406-021-01286-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 06/21/2021] [Indexed: 12/15/2022]
Abstract
Recently, much attention has been drawn to the importance of the impact of infectious disease on human cognition. Several theories have been proposed, to explain the cognitive decline following an infection as well as to understand better the pathogenesis of human dementia, especially Alzheimer's disease. This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.
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Affiliation(s)
- Rodolfo Furlan Damiano
- Departamento E Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César, São Paulo, SP, 05403-903, Brazil.
| | - Bruno F. Guedes
- Department of Neurology, University of São Paulo, São Paulo, Brazil
| | - Cristiana Castanho de Rocca
- Departamento E Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César, São Paulo, SP 05403-903 Brazil
| | - Antonio de Pádua Serafim
- Departamento E Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César, São Paulo, SP 05403-903 Brazil
| | | | - Carolina Demarchi Munhoz
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ricardo Nitrini
- Department of Neurology, University of São Paulo, São Paulo, Brazil
| | - Geraldo Busatto Filho
- Departamento E Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César, São Paulo, SP 05403-903 Brazil
| | - Eurípedes Constantino Miguel
- Departamento E Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César, São Paulo, SP 05403-903 Brazil
| | - Giancarlo Lucchetti
- Department of Medicine, Federal University of Juiz de Fora, Juiz de Fora, Brazil
| | - Orestes Forlenza
- Departamento E Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Rua Dr. Ovídio Pires de Campos, 785, Cerqueira César, São Paulo, SP 05403-903 Brazil
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40
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Fearon C, Fasano A. Prevalence and outcomes of Covid-19 in Parkinson's disease: Acute settings and hospital. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 165:35-62. [PMID: 36208906 PMCID: PMC9020798 DOI: 10.1016/bs.irn.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The global explosion of COVID-19 necessitated the rapid dissemination of information regarding SARS-CoV-2. Hence, COVID-19 prevalence and outcome data in Parkinson's disease patients were disseminated at a time when we only had part of the picture. In this chapter we firstly discuss the current literature on the prevalence of COVID-19 in people with PD. We then discuss outcomes from COVID-19 in people with PD, specifically risk of hospitalization and mortality. Finally, we discuss specific contributing and confounding factors which may put PD patients at higher or lower risk from COVID-19.
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Affiliation(s)
- Conor Fearon
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital-UHN, Division of Neurology, University of Toronto, Toronto, ON, Canada
| | - Alfonso Fasano
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital-UHN, Division of Neurology, University of Toronto, Toronto, ON, Canada; Krembil Research Institute, Toronto, ON, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada.
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Toft-Bertelsen TL, Jeppesen MG, Tzortzini E, Xue K, Giller K, Becker S, Mujezinovic A, Bentzen BH, B Andreas L, Kolocouris A, Kledal TN, Rosenkilde MM. Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2. Commun Biol 2021; 4:1347. [PMID: 34853399 PMCID: PMC8636635 DOI: 10.1038/s42003-021-02866-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 11/02/2021] [Indexed: 12/16/2022] Open
Abstract
The dire need for COVID-19 treatments has inspired strategies of repurposing approved drugs. Amantadine has been suggested as a candidate, and cellular as well as clinical studies have indicated beneficial effects of this drug. We demonstrate that amantadine and hexamethylene-amiloride (HMA), but not rimantadine, block the ion channel activity of Protein E from SARS-CoV-2, a conserved viroporin among coronaviruses. These findings agree with their binding to Protein E as evaluated by solution NMR and molecular dynamics simulations. Moreover, we identify two novel viroporins of SARS-CoV-2; ORF7b and ORF10, by showing ion channel activity in a X. laevis oocyte expression system. Notably, amantadine also blocks the ion channel activity of ORF10, thereby providing two ion channel targets in SARS-CoV-2 for amantadine treatment in COVID-19 patients. A screen of known viroporin inhibitors on Protein E, ORF7b, ORF10 and Protein 3a from SARS-CoV-2 revealed inhibition of Protein E and ORF7b by emodin and xanthene, the latter also blocking Protein 3a. This illustrates a general potential of well-known ion channel blockers against SARS-CoV-2 and specifically a dual molecular basis for the promising effects of amantadine in COVID-19 treatment. We therefore propose amantadine as a novel, cheap, readily available and effective way to treat COVID-19.
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Affiliation(s)
- Trine Lisberg Toft-Bertelsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mads Gravers Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Synklino ApS, Charlottenlund, Denmark
| | - Eva Tzortzini
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens, Greece
| | - Kai Xue
- Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Karin Giller
- Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Stefan Becker
- Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Amer Mujezinovic
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bo Hjorth Bentzen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Loren B Andreas
- Department of NMR-based structural biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Antonios Kolocouris
- Laboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, Athens, Greece
| | | | - Mette Marie Rosenkilde
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Ahmed A, Saeed A, Ali OM, El-Bahy ZM, Channar PA, Khurshid A, Tehzeeb A, Ashraf Z, Raza H, Ul-Hamid A, Hassan M. Exploring Amantadine Derivatives as Urease Inhibitors: Molecular Docking and Structure-Activity Relationship (SAR) Studies. Molecules 2021; 26:molecules26237150. [PMID: 34885728 PMCID: PMC8658948 DOI: 10.3390/molecules26237150] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/21/2021] [Accepted: 11/22/2021] [Indexed: 11/24/2022] Open
Abstract
This article describes the design and synthesis of a series of novel amantadine-thiourea conjugates (3a–j) as Jack bean urease inhibitors. The synthesized hybrids were assayed for their in vitro urease inhibition. Accordingly, N-(adamantan-1-ylcarbamothioyl)octanamide (3j) possessing a 7-carbon alkyl chain showed excellent activity with IC50 value 0.0085 ± 0.0011 µM indicating that the long alkyl chain plays a vital role in enzyme inhibition. Whilst N-(adamantan-1-ylcarbamothioyl)-2-chlorobenzamide (3g) possessing a 2-chlorophenyl substitution was the next most efficient compound belonging to the aryl series with IC50 value of 0.0087 ± 0.001 µM. The kinetic mechanism analyzed by Lineweaver–Burk plots revealed the non-competitive mode of inhibition for compound 3j. Moreover, in silico molecular docking against target protein (PDBID 4H9M) indicated that most of the synthesized compounds exhibit good binding affinity with protein. The compound 3j forms two hydrogen bonds with amino acid residue VAL391 having a binding distance of 1.858 Å and 2.240 Å. The interaction of 3j with amino acid residue located outside the catalytic site showed its non-competitive mode of inhibition. Based upon these results, it is anticipated that compound 3j may serve as a lead structure for the design of more potent urease inhibitors.
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Affiliation(s)
- Atteeque Ahmed
- Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan; (A.A.); (P.A.C.); (A.K.)
| | - Aamer Saeed
- Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan; (A.A.); (P.A.C.); (A.K.)
- Correspondence: or ; Tel.: +92-51-9064-2128
| | - Omar M. Ali
- Department of Chemistry, Turabah University College, Turabah Branch, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Zeinhom M. El-Bahy
- Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo 11884, Egypt;
| | - Pervaiz Ali Channar
- Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan; (A.A.); (P.A.C.); (A.K.)
| | - Asma Khurshid
- Department of Chemistry, Quaid-I-Azam University, Islamabad 45320, Pakistan; (A.A.); (P.A.C.); (A.K.)
| | - Arfa Tehzeeb
- Department of Pharmacy, Quaid-i-Azam University, Islamabad 45320, Pakistan;
| | - Zaman Ashraf
- Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan;
| | - Hussain Raza
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, 56 Gongjudehak-Ro, Gongju 314-701, Chungnam, Korea;
| | - Anwar Ul-Hamid
- Core Research Facilities, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia;
| | - Mubashir Hassan
- Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan;
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Zalyalova ZA, Khasanova DM. [Risk and course of COVID-19 in patients with Parkinson's disease]. Zh Nevrol Psikhiatr Im S S Korsakova 2021; 121:152-156. [PMID: 34693704 DOI: 10.17116/jnevro2021121091152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The article provides an overview of the data on the impact of Parkinson's disease on the risk of infection and the course of COVID-19, and also assesses the possible pathogenetic relationship between the SARS-CoV-2 virus, COVID-19 and PD. By penetrating the central nervous system, SARS-CoV-2 can cause not only neurological symptoms, but also exacerbate the course of an existing neurological disease. The impact of Parkinson's disease on the risk of infection and the course of COVID-19 is controversial. However, a number of authors support the opinion that PD is an anti-risk factor for the development of COVID-19, which is associated both with the pathogenesis of the disease and with the used antiparkinsonian drugs, in particular amantadines. There are no clear data indicating higher risk of infection and higher severity of COVID-19 in patients with PD. On the contrary, experimental and clinical data suggest a possible modifying role of α-synuclein and antiparkinsonian drugs.
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Affiliation(s)
- Z A Zalyalova
- Kazan State Medical University, Kazan, Russia.,Rebublican Center for Movement Disorders, Kazan, Russia.,Hospital for War Veterans, Kazan, Russia
| | - D M Khasanova
- Rebublican Center for Movement Disorders, Kazan, Russia.,Hospital for War Veterans, Kazan, Russia
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Kamel WA, Kamel MI, Alhasawi A, Elmasry S, AlHamdan F, Al-Hashel JY. Effect of Pre-exposure Use of Amantadine on COVID-19 Infection: A Hospital-Based Cohort Study in Patients With Parkinson's Disease or Multiple Sclerosis. Front Neurol 2021; 12:704186. [PMID: 34690911 PMCID: PMC8529185 DOI: 10.3389/fneur.2021.704186] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 09/07/2021] [Indexed: 11/28/2022] Open
Abstract
Background: Amantadine has been proposed to inhibit E-channel conductance in reconstituted lipid bilayers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to study whether patients on amantadine have altered risks of contracting COVID-19 infection. Methods: We conducted a hospital-based, observational, retrospective cohort study using data for patients on amantadine supported by data given by the patients through an online questionnaire. We included registered amantadine users in our hospital for 6 months or more on March 1, 2020, and non-amantadine users to act as the control group. We used forced entry, multiple logistic regression models to estimate adjusted ORs for amantadine adjusting for the confounders. Findings: Between September 1, 2019, and March 1, 2020, 212 patients with Parkinson's disease (PD) or multiple sclerosis (MS) received greater than one equal to two prescriptions of amantadine. We selected a random sample of diagnoses which matched 424 patients of non-amantadine users (1:2) as a control group (424 patients). Between March 1, 2020, and March 1, 2021, 256 patients responded to our online questionnaire, 87 patients were on amantadine (group I), and 169 patients were not (control group, group II). COVID-19 disease infection proved to be 5.7 and 11.8% in group I and II patients, respectively. Increased odds of COVID-19 in multivariable-adjusted models were associated with old age and history of contact with COVID cases. Amantadine was associated with a significantly reduced risk of COVID-19 disease infection (adjusted OR 0.256, 95% CI 0.074–0.888). Interpretation: Amantadine is associated with a reduced risk of COVID-19 infection after adjusting for a broad range of variables. History of contact with COVID cases and old age are risk factors for COVID-19 infection. Therefore, we recommended randomized clinical trials investigating amantadine use for the prevention of COVID-19.
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Affiliation(s)
- Walaa A Kamel
- Neurology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.,Neurology Department, Ibn-Sina Hospital, Kuwait City, Kuwait
| | - Mohmed I Kamel
- Occupational and Environmental Medicine, Alexandria University, Alexandria, Egypt
| | - Almunther Alhasawi
- Internal Medicine and Infectious Diseases Consultant, Infectious Disease Hospital, Kuwait City, Kuwait
| | - Sameh Elmasry
- Internal Medicine and Infectious Diseases Consultant, Infectious Disease Hospital, Kuwait City, Kuwait
| | - Fajer AlHamdan
- Internal Medicine Department, Al-Sabah Hospital, Kuwait City, Kuwait
| | - Jasem Y Al-Hashel
- Neurology Department, Ibn-Sina Hospital, Kuwait City, Kuwait.,Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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45
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Berdowska I, Matusiewicz M. Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract. World J Gastroenterol 2021; 27:6590-6600. [PMID: 34754154 PMCID: PMC8554394 DOI: 10.3748/wjg.v27.i39.6590] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 06/28/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seems to employ two routes of entrance to the host cell; via membrane fusion (with the cells expressing both angiotensin converting enzyme 2 (ACE2) and transmembrane peptidase/serine subfamily member 2/4 (TMPRSS2/4)) or via receptor-mediated endocytosis (to the target cells expressing only ACE2). The second mode is associated with cysteine cathepsins (probably cathepsin L) involvement in the virus spike protein (S protein) proteolytic activation. Also furin might activate the virus S protein enabling it to enter cells. Gastrointestinal tract (GIT) involvement in SARS-CoV-2 infection is evident in a subset of coronavirus disease 2019 (COVID-19) patients exhibiting GIT symptoms, such as diarrhea, and presenting viral-shedding in feces. Considering the abundance and co-localization of ACE2 and TMPRSS2 in the lower GIT (especially brush-border enterocytes), these two receptors seem to be mainly involved in SARS-CoV-2 invasion of the digestive tract. Additionally, in vitro studies have demonstrated the virions capability of infection and replication in the human epithelial cells lining GIT. However, also furin and cysteine cathepsins (cathepsin L) might participate in the activation of SARS-CoV-2 spike protein contributing to the virus invasiveness within GIT. Moreover, cathepsin L (due to its involvement in extracellular matrix components degradation and remodeling, the processes enhanced during SARS-CoV-2-induced inflammation) might be responsible for the dysregulation of absorption/ digestion functions of GIT, thus adding to the observed in some COVID-19 patients symptoms such as diarrhea.
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Affiliation(s)
- Izabela Berdowska
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wroclaw 50-368, Lower Silesia, Poland
| | - Malgorzata Matusiewicz
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wroclaw 50-368, Lower Silesia, Poland
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Zhou Y, Gammeltoft KA, Galli A, Offersgaard A, Fahnøe U, Ramirez S, Bukh J, Gottwein JM. Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro. Viruses 2021; 13:v13102082. [PMID: 34696509 PMCID: PMC8537953 DOI: 10.3390/v13102082] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/24/2021] [Accepted: 10/05/2021] [Indexed: 11/24/2022] Open
Abstract
We report the in vitro efficacy of ion-channel inhibitors amantadine, memantine and rimantadine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In VeroE6 cells, rimantadine was most potent followed by memantine and amantadine (50% effective concentrations: 36, 80 and 116 µM, respectively). Rimantadine also showed the highest selectivity index, followed by amantadine and memantine (17.3, 12.2 and 7.6, respectively). Similar results were observed in human hepatoma Huh7.5 and lung carcinoma A549-hACE2 cells. Inhibitors interacted in a similar antagonistic manner with remdesivir and had a similar barrier to viral escape. Rimantadine acted mainly at the viral post-entry level and partially at the viral entry level. Based on these results, rimantadine showed the most promise for treatment of SARS-CoV-2.
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Affiliation(s)
- Yuyong Zhou
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Karen A. Gammeltoft
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Andrea Galli
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Anna Offersgaard
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Ulrik Fahnøe
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Santseharay Ramirez
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Judith M. Gottwein
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital-Hvidovre, Kettegård Alle 30, 2650 Hvidovre, Denmark; (Y.Z.); (K.A.G.); (A.G.); (A.O.); (U.F.); (S.R.); (J.B.)
- Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
- Correspondence:
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Myocardial Damage by SARS-CoV-2: Emerging Mechanisms and Therapies. Viruses 2021; 13:v13091880. [PMID: 34578462 PMCID: PMC8473126 DOI: 10.3390/v13091880] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/06/2021] [Accepted: 09/18/2021] [Indexed: 01/01/2023] Open
Abstract
Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.
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48
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COVID-19 manifestations in people with Parkinson's disease: a USA cohort. J Neurol 2021; 269:1107-1113. [PMID: 34482434 PMCID: PMC8418279 DOI: 10.1007/s00415-021-10784-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 07/16/2021] [Accepted: 08/29/2021] [Indexed: 12/22/2022]
Abstract
Background With the explosion of COVID-19 globally, it was unclear if people with Parkinson’s disease (PD) were at increased risk for severe manifestations or negative outcomes. Objectives To report on people with PD who had suspected or confirmed COVID-19 to understand how COVID-19 manifested in PD patients. Methods We surveyed PD patients who reported COVID-19 to their Movement Disorders specialists at Columbia University Irving Medical Center and respondents from an online survey administered by the Parkinson’s Foundation that assessed COVID-19 symptoms, general clinical outcomes and changes in motor and non-motor PD symptoms. Results Forty-six participants with PD and COVID-19 were enrolled. Similar to the general population, the manifestations of COVID-19 among people with PD were heterogeneous ranging from asymptomatic carriers (1/46) to death (6/46). The most commonly reported COVID-19 symptoms were fever/chills, fatigue, cough, weight loss, and muscle pain. Worsening and new onset of motor and non-motor PD symptoms during COVID-19 illness were also reported, including dyskinesia, rigidity, balance disturbances, anxiety, depression, and insomnia. Conclusion We did not find sufficient evidence that PD is an independent risk factor for severe COVID-19 and death. Larger studies with controls are required to understand this further. Longitudinal follow-up of these participants will allow for observation of possible long-term effects of COVID-19 in PD patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-021-10784-3.
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Abstract
Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human respiratory coronavirus HCoV-OC43, bovine coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and a spiroadamantane amine is effective against the coronavirus strain 229E. Molecular docking studies suggest that amantadine may block the viral E protein channel, leading to impaired viral propagation. Additionally, amantadine analogues may inhibit entry of the virus into the host cell by increasing the pH of the endosomes and thus inhibiting the action of host cell proteases such as Cathepsin L. High-throughput drug screen gene expression analysis identified compounds able to down-regulate Cathepsin L expression where the fifth most potent agent of 466 candidates was amantadine. Amantadine inhibits severe acute respiratory syndrome coronavirus 2 replication in vitro but does not inhibit the binding of the spike protein to ACE2. Adamantanes also may act against coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via antagonism of glutamate (NMDA) and the α-7 subtype of the nicotinic acetylcholine receptor located on bronchial and alveolar epithelial cells. As an NMDA receptor antagonist, memantine has the potential to inhibit entry of SARS-CoV-2 into these cell populations. Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadine has been entertained. Case reports involving 23 patients with reverse transcription polymerase chain reaction-confirmed coronavirus disease 2019 (COVID-19) and a range of co-morbidities including type 2 diabetes mellitus, Parkinson's disease, multiple sclerosis and severe cognitive impairment reveal significant potential benefits of amantadine and memantine for the prevention and/or treatment of coronavirus disease 2019 and its neurological complications.
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Affiliation(s)
- Roger F Butterworth
- Department of Medicine, University of Montreal, 45143 Cabot Trail, Englishtown, NS, B0C 1H0, Canada.
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50
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Zsidó B, Börzsei R, Szél V, Hetényi C. Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning. J Chem Inf Model 2021; 61:4011-4022. [PMID: 34313421 PMCID: PMC8389532 DOI: 10.1021/acs.jcim.1c00488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Indexed: 12/29/2022]
Abstract
Target-based design and repositioning are mainstream strategies of drug discovery. Numerous drug design and repositioning projects have been launched to fight the ongoing COVID-19 pandemic. The resulting drug candidates have often failed due to the misprediction of their target-bound structures. The determination of water positions of such structures is particularly challenging due to the large number of possible drugs and the diversity of their hydration patterns. To answer this challenge and help correct predictions, we introduce a new protocol HydroDock, which can build hydrated drug-target complexes from scratch. HydroDock requires only the dry target and drug structures and produces their complexes with appropriately positioned water molecules. As a test application of the protocol, we built the structures of amantadine derivatives in complex with the influenza M2 transmembrane ion channel. The repositioning of amantadine derivatives from this influenza target to the SARS-CoV-2 envelope protein was also investigated. Excellent agreement was observed between experiments and the structures determined by HydroDock. The atomic resolution complex structures showed that water plays a similar role in the binding of amphipathic amantadine derivatives to transmembrane ion channels of both influenza A and SARS-CoV-2. While the hydrophobic regions of the channels capture the bulky hydrocarbon group of the ligand, the surrounding waters direct its orientation parallel with the axes of the channels via bridging interactions with the ionic ligand head. As HydroDock supplied otherwise undetermined structural details, it can be recommended to improve the reliability of future design and repositioning of antiviral drug candidates and many other ligands with an influence of water structure on their mechanism of action.
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Affiliation(s)
- Balázs
Zoltán Zsidó
- Pharmacoinformatics
Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
| | - Rita Börzsei
- Pharmacoinformatics
Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
- Department
of Pharmacology, Faculty of Pharmacy, University
of Pécs, Szigeti
út 12, 7624 Pécs, Hungary
| | - Viktor Szél
- Pharmacoinformatics
Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
| | - Csaba Hetényi
- Pharmacoinformatics
Unit, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
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