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Li Y, Yang S, Jiang F, Luo S, Liang J, Jiang L, Chen Z, Chen X, Yang J. Cilnidipine exerts antiviral effects in vitro and in vivo by inhibiting the internalization and fusion of influenza A virus. BMC Med 2025; 23:200. [PMID: 40189517 PMCID: PMC11974063 DOI: 10.1186/s12916-025-04022-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/19/2025] [Indexed: 04/09/2025] Open
Abstract
BACKGROUND Influenza A virus (IAV) is a major cause of seasonal and global pandemics, posing serious health risks. Repositioning approved drugs offers an efficient antiviral strategy, particularly as calcium (Ca2⁺) is crucial for IAV infection, making Ca2⁺ channel blockers (CCBs) promising candidates for antiviral agents. METHODS The in vitro antiviral activity of cilnidipine was evaluated using MTT assays, qRT-PCR, plaque assays, and western blotting. Mechanistic studies involved time-of-addition, viral internalization, pseudovirus neutralization, and HA (hemagglutinin) syncytium assays. For in vivo analysis, BALB/c mice were intranasally infected to evaluate the effects of cilnidipine on viral titer, lung index, pulmonary inflammatory mediators, and survival rate. RESULTS In vitro, cilnidipine exhibits antiviral activity against IAV during the early stages of infection. It disrupts clathrin- and caveolin-mediated endocytosis to inhibit the internalization of IAV and interacts with the viral HA2 subunit to impede virus membrane fusion. Additionally, cilnidipine suppresses the PI3K-AKT and p38 MAPK pathways activated by IAV infections. In vivo, cilnidipine reduces virus titers and lung index, ameliorates lung pathology, and inhibits pulmonary inflammatory mediator expression, improving survival rates. CONCLUSIONS These findings highlight the promising anti-IAV properties of cilnidipine both in vitro and in vivo, suggesting its potential as a clinical agent for emergencies against influenza outbreaks.
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Affiliation(s)
- Yinyan Li
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Sizu Yang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Feng Jiang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Siqi Luo
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jinlong Liang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Linrui Jiang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Zhixuan Chen
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Xin Chen
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
| | - Jie Yang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
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D’Elia JA, Weinrauch LA. Role of Divalent Cations in Infections in Host-Pathogen Interaction. Int J Mol Sci 2024; 25:9775. [PMID: 39337264 PMCID: PMC11432163 DOI: 10.3390/ijms25189775] [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: 07/29/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
With increasing numbers of patients worldwide diagnosed with diabetes mellitus, renal disease, and iatrogenic immune deficiencies, an increased understanding of the role of electrolyte interactions in mitigating pathogen virulence is necessary. The levels of divalent cations affect host susceptibility and pathogen survival in persons with relative immune insufficiency. For instance, when host cellular levels of calcium are high compared to magnesium, this relationship contributes to insulin resistance and triples the risk of clinical tuberculosis. The movement of divalent cations within intracellular spaces contributes to the host defense, causing apoptosis or autophagy of the pathogen. The control of divalent cation flow is dependent in part upon the mammalian natural resistance-associated macrophage protein (NRAMP) in the host. Survival of pathogens such as M tuberculosis within the bronchoalveolar macrophage is also dependent upon NRAMP. Pathogens evolve mutations to control the movement of calcium through external and internal channels. The host NRAMP as a metal transporter competes for divalent cations with the pathogen NRAMP in M tuberculosis (whether in latent, dormant, or active phase). This review paper summarizes mechanisms of pathogen offense and patient defense using inflow and efflux through divalent cation channels under the influence of parathyroid hormone vitamin D and calcitonin.
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Affiliation(s)
| | - Larry A. Weinrauch
- Kidney and Hypertension Section, E P Joslin Research Laboratory, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Chen F, Shen H, Liu G, Zhang P, Zhang L, Lin S, Gao H, Peng H, Qi YF, Chen Y, Jiang Y, Huang J, Shen X, Luo YS, Zhang K. Verapamil inhibits respiratory syncytial virus infection by regulating Ca 2+ influx. Life Sci 2024; 352:122877. [PMID: 38942358 DOI: 10.1016/j.lfs.2024.122877] [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: 01/23/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
AIMS The study evaluated the antiviral effect of Verapamil against respiratory syncytial virus (RSV) and investigated its underlying mechanism. MATERIALS AND METHODS RSV-infected BALB/c mice were treated with Verapamil. Body weight, survival rates, viral load, lung damage, inflammatory factors, and the expression of RSV fusion (F) protein were analyzed. In cellular studies, intracellular Ca2+ and viral titers were measured in the presence of Verapamil, Calcium Chloride, and EGTA. A time-of-addition assay assessed the antiviral effect of Verapamil. KEY FINDINGS Mice infected with RSV and treated with Verapamil exhibited a significant decrease in weight loss, an increase in survival rates, and reductions in viral titers, RSV F protein expression, inflammatory responses, and lung tissue injury. Verapamil reduced intracellular calcium levels, which correlated with reduced viral titers. The addition of calcium chloride reversed the anti-viral effects mediated by Verapamil, while EGTA potentiated them. The antiviral activity of Verapamil was observed during the early phase of RSV infection, likely by blocking Ca2+ channels and inhibiting virus replication. SIGNIFICANCE Verapamil effectively inhibits RSV infection by blocking calcium channels and reducing intracellular calcium levels, thereby impeding viral replication. Thus, Verapamil shows promise as a treatment for RSV.
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Affiliation(s)
- Fang Chen
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China
| | - Huyan Shen
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China
| | - Gang Liu
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China
| | - Pingping Zhang
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China
| | - Lin Zhang
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China
| | - Siyu Lin
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China
| | - Han Gao
- Emergency ICU, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Hong Peng
- Emergency ICU, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Yan-Fei Qi
- Department of Pharmacology, College of Osteopathic Medicine, Duquesne University, Pittsburgh, PA 15219, USA
| | - Yan Chen
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China
| | - Yinhui Jiang
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Ministry of Education, Guiyang 550004, China
| | - Jiandong Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Xiangchun Shen
- The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China
| | - Yu-Si Luo
- Emergency ICU, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; Department of Emergency, Liupanshui Hospital of The Affiliated Hospital of Guizhou Medical University, Liupanshui 553000, China.
| | - Ke Zhang
- Key Laboratory of Microbio and Infectious Disease Prevention & Control in Guizhou Province / Institute of Virology / The Key and Characteristic Laboratory of Modern Pathogenicity Biology, Department of Pharmacology, School of Basic Medicine, Guizhou Medical University, Guiyang 561113, China; The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang 561113, China.
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Frazer JS, Lucas-Evans R, Dayala A, Mlangeni DA. Changes in arterial pH do not explain the reductions in ionised calcium observed during COVID-19 infection. Adv Med Sci 2024; 69:51-55. [PMID: 38364757 DOI: 10.1016/j.advms.2024.02.001] [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: 10/19/2023] [Revised: 12/20/2023] [Accepted: 02/02/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND Hypocalcaemia predicts coronavirus disease 2019 (COVID-19) severity and mortality. We hypothesized an association between respiratory alkalosis secondary to hypoxia and low ionised calcium (iCa) concentration in patients with COVID-19. METHODS Arterial blood gas samples taken from January 2019 to March 2021 were retrospectively matched with infection status. Principal components regression was undertaken to determine the correlation between pH, partial pressure arterial oxygen (PaO2), partial pressure arterial carbon dioxide (PaCO2), and iCa. RESULTS We included 4056 patients (300 COVID-19 detected, 19 influenza detected), corresponding to 5960 arterial blood samples. The COVID-19 detected group had a statistically significantly lower iCa, PaO2 and PaCO2, and more alkalotic pH than infection-free groups. The influenza group had a lower iCa and PaCO2, higher PaO2, and a more alkalotic pH than infection-free groups, but these differences were non-significant. Principal components regression revealed that pH, PaCO2, and PaO2 explain just 2.72 % of the variance in iCa. An increase in pH by 1 unit was associated with an iCa reduction of 0.141 mmol/L (p < 0.0001). CONCLUSION Reduction in iCa concentration in patients with COVID-19 is not associated with pH derangement. Influenza infection was associated with a minor reduction in iCa in our small sample, a hitherto unreported finding, although statistical significance was not demonstrated.
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Affiliation(s)
- John Scott Frazer
- North West Anglia NHS Foundation Trust, Bretton Gate, Bretton, Peterborough, United Kingdom.
| | - Robin Lucas-Evans
- North West Anglia NHS Foundation Trust, Bretton Gate, Bretton, Peterborough, United Kingdom
| | - Asghar Dayala
- North West Anglia NHS Foundation Trust, Bretton Gate, Bretton, Peterborough, United Kingdom
| | - Dennis A Mlangeni
- North West Anglia NHS Foundation Trust, Bretton Gate, Bretton, Peterborough, United Kingdom
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5
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Bond ACS, Crocker MA, Wilczek MP, DuShane JK, Sandberg AL, Bennett LJ, Leclerc NR, Maginnis MS. High-throughput drug screen identifies calcium and calmodulin inhibitors that reduce JCPyV infection. Antiviral Res 2024; 222:105817. [PMID: 38246207 PMCID: PMC10922812 DOI: 10.1016/j.antiviral.2024.105817] [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: 11/18/2023] [Revised: 01/09/2024] [Accepted: 01/18/2024] [Indexed: 01/23/2024]
Abstract
JC polyomavirus (JCPyV) is a nonenveloped, double-stranded DNA virus that infects the majority of the population. Immunocompetent individuals harbor infection in their kidneys, while severe immunosuppression can result in JCPyV spread to the brain, causing the neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Due to a lack of approved therapies to treat JCPyV and PML, the disease results in rapid deterioration, and is often fatal. In order to identify potential antiviral treatments for JCPyV, a high-throughput, large-scale drug screen was performed using the National Institutes of Health Clinical Collection (NCC). Drugs from the NCC were tested for inhibitory effects on JCPyV infection, and drugs from various classes that reduced JCPyV infection were identified, including receptor agonists and antagonists, calcium signaling modulators, and enzyme inhibitors. Given the role of calcium signaling in viral infection including Merkel cell polyomavirus and simian virus 40 polyomavirus (SV40), calcium signaling inhibitors were further explored for the capacity to impact JCPyV infection. Calcium and calmodulin inhibitors trifluoperazine (TFP), W-7, tetrandrine, and nifedipine reduced JCPyV infection, and TFP specifically reduced viral internalization. Additionally, TFP and W-7 reduced infection by BK polyomavirus, SV40, and SARS-CoV-2. These results highlight specific inhibitors, some FDA-approved, for the possible treatment and prevention of JCPyV and several other viruses, and further illuminate the calcium and calmodulin pathway as a potential target for antiviral drug development.
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Affiliation(s)
- Avery C S Bond
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Mason A Crocker
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Michael P Wilczek
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Jeanne K DuShane
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Amanda L Sandberg
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Lucas J Bennett
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Nicholas R Leclerc
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA
| | - Melissa S Maginnis
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, 04469, USA; Graduate School of Biomedical Science and Engineering, Orono, ME, 04469, USA.
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Bergantin L. Ca 2+/cAMP ratio: An inflammatory index for diabetes, hypertension, and COVID-19. World J Diabetes 2023; 14:343-346. [PMID: 37035235 PMCID: PMC10075043 DOI: 10.4239/wjd.v14.i3.343] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/11/2022] [Accepted: 02/08/2023] [Indexed: 03/15/2023] Open
Abstract
Ca2+/cAMP ratio could serve as an inflammatory index for diseases like hyp-ertension, diabetes, and coronavirus disease 2019.
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Affiliation(s)
- Leandro Bergantin
- Department of Pharmacology, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil
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7
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Loh KWZ, Hu Z, Soong TW. Modulation of Ca V1.2 Channel Function by Interacting Proteins and Post-Translational Modifications: Implications in Cardiovascular Diseases and COVID-19. Handb Exp Pharmacol 2023. [PMID: 36764970 DOI: 10.1007/164_2023_636] [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: 02/12/2023]
Abstract
CaV1.2 calcium channel is the primary conduit for Ca2+ influx into cardiac and smooth muscles that underscores its importance in the pathogenesis of hypertension, atherosclerosis, myocardial infarction, and heart failure. But, a few controversies still remain. Therefore, exploring new ways to modulate CaV1.2 channel activity will augment the arsenal of CaV1.2 channel-based therapeutics for treatment of cardiovascular diseases. Here, we will mainly introduce a couple of emerging CaV1.2 channel interacting proteins, such as Galectin-1 and Cereblon, and discuss their roles in hypertension and heart failure through fine-tuning CaV1.2 channel activity. Of current interest, we will also evaluate the implication of the role of CaV1.2 channel in SARS-CoV-2 infection and the potential treatments of COVID-19-related cardiovascular symptoms.
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Affiliation(s)
- Kelvin Wei Zhern Loh
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Cardiovascular Diseases Translational Research Programme, National University of Singapore, Singapore, Singapore
| | - Zhenyu Hu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Cardiovascular Diseases Translational Research Programme, National University of Singapore, Singapore, Singapore
| | - Tuck Wah Soong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Cardiovascular Diseases Translational Research Programme, National University of Singapore, Singapore, Singapore. .,Healthy Longevity Translational Research Programme, National University of Singapore, Singapore, Singapore.
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8
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Bergantin LB. Ca 2+/cAMP Ratio as an Inflammatory Index. Curr Hypertens Rev 2023; 19:4-6. [PMID: 36476433 DOI: 10.2174/1573402119666221202145753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 11/05/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022]
Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, Vila Clementino, São Paulo, SP, Brazil
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9
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Phenothiazines inhibit SARS-CoV-2 cell entry via a blockade of spike protein binding to neuropilin-1. Antiviral Res 2023; 209:105481. [PMID: 36481388 PMCID: PMC9721373 DOI: 10.1016/j.antiviral.2022.105481] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/02/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells using angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) as the primary receptor and entry co-factor, respectively. Cell entry is the first and major step in initiation of the viral life cycle, representing an ideal target for antiviral interventions. In this study, we used a recombinant replication-deficient vesicular stomatitis virus-based pseudovirus bearing the spike protein of SARS-CoV-2 (SARS2-S) to screen a US Food and Drug Administration-approved drug library and identify inhibitors of SARS-CoV-2 cell entry. The screen identified 24 compounds as primary hits, and the largest therapeutic target group formed by these primary hits was composed of seven dopamine receptor D2 (DRD2) antagonists. Cell-based and biochemical assays revealed that the DRD2 antagonists inhibited both fusion activity and the binding of SARS2-S to NRP-1, but not its binding to ACE2. On the basis of structural similarity to the seven identified DRD2 antagonists, which included six phenothiazines, we examined the anti-SARS-CoV-2 activity of an additional 15 phenothiazines and found that all the tested phenothiazines shared an ability to inhibit SARS2-S-mediated cell entry. One of the phenothiazines, alimemazine, which had the lowest 50% effective concentration of the tested phenothiazines, exhibited a clear inhibitory effect on SARS2-S-NRP-1 binding and SARS-CoV-2 multiplication in cultured cells but not in a mouse infection model. Our findings provide a basis for the development of novel anti-SARS-CoV-2 therapeutics that interfere with SARS2-S binding to NRP-1.
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10
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Huang Y, Li Y, Chen Z, Chen L, Liang J, Zhang C, Zhang Z, Yang J. Nisoldipine Inhibits Influenza A Virus Infection by Interfering with Virus Internalization Process. Viruses 2022; 14:v14122738. [PMID: 36560742 PMCID: PMC9785492 DOI: 10.3390/v14122738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/29/2022] [Accepted: 12/03/2022] [Indexed: 12/14/2022] Open
Abstract
Influenza virus infections and the continuing spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are global public health concerns. As there are limited therapeutic options available in clinical practice, the rapid development of safe, effective and globally available antiviral drugs is crucial. Drug repurposing is a therapeutic strategy used in treatments for newly emerging and re-emerging infectious diseases. It has recently been shown that the voltage-dependent Ca2+ channel Cav1.2 is critical for influenza A virus entry, providing a potential target for antiviral strategies. Nisoldipine, a selective Ca2+ channel inhibitor, is commonly used in the treatment of hypertension. Here, we assessed the antiviral potential of nisoldipine against the influenza A virus and explored the mechanism of action of this compound. We found that nisoldipine treatment could potently inhibit infection with multiple influenza A virus strains. Mechanistic studies further revealed that nisoldipine impaired the internalization of the influenza virus into host cells. Overall, our findings demonstrate that nisoldipine exerts antiviral effects against influenza A virus infection and could serve as a lead compound in the design and development of new antivirals.
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Affiliation(s)
| | | | | | | | | | | | | | - Jie Yang
- Correspondence: ; Tel.: +86-020-6164-8590
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11
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Russell T, Gangotia D, Barry G. Assessing the potential of repurposing ion channel inhibitors to treat emerging viral diseases and the role of this host factor in virus replication. Biomed Pharmacother 2022; 156:113850. [DOI: 10.1016/j.biopha.2022.113850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/25/2022] [Accepted: 10/06/2022] [Indexed: 12/03/2022] Open
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12
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Nguyenla X, Wehri E, Van Dis E, Biering SB, Yamashiro LH, Zhu C, Stroumza J, Dugast-Darzacq C, Graham TGW, Wang X, Jockusch S, Tao C, Chien M, Xie W, Patel DJ, Meyer C, Garzia A, Tuschl T, Russo JJ, Ju J, Näär AM, Stanley S, Schaletzky J. Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells. Sci Rep 2022; 12:18506. [PMID: 36323770 PMCID: PMC9628577 DOI: 10.1038/s41598-022-21034-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/21/2022] [Indexed: 11/07/2022] Open
Abstract
SARS coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic with significant mortality and morbidity. At this time, the only FDA-approved therapeutic for COVID-19 is remdesivir, a broad-spectrum antiviral nucleoside analog. Efficacy is only moderate, and improved treatment strategies are urgently needed. To accomplish this goal, we devised a strategy to identify compounds that act synergistically with remdesivir in preventing SARS-CoV-2 replication. We conducted combinatorial high-throughput screening in the presence of submaximal remdesivir concentrations, using a human lung epithelial cell line infected with a clinical isolate of SARS-CoV-2. This identified 20 approved drugs that act synergistically with remdesivir, many with favorable pharmacokinetic and safety profiles. Strongest effects were observed with established antivirals, Hepatitis C virus nonstructural protein 5A (HCV NS5A) inhibitors velpatasvir and elbasvir. Combination with their partner drugs sofosbuvir and grazoprevir further increased efficacy, increasing remdesivir's apparent potency > 25-fold. We report that HCV NS5A inhibitors act on the SARS-CoV-2 exonuclease proofreader, providing a possible explanation for the synergy observed with nucleoside analog remdesivir. FDA-approved Hepatitis C therapeutics Epclusa® (velpatasvir/sofosbuvir) and Zepatier® (elbasvir/grazoprevir) could be further optimized to achieve potency and pharmacokinetic properties that support clinical evaluation in combination with remdesivir.
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Affiliation(s)
- Xammy Nguyenla
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA
| | - Eddie Wehri
- The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA
| | - Erik Van Dis
- Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA
| | - Scott B Biering
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA
| | - Livia H Yamashiro
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA
- Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA
| | - Chi Zhu
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA
| | - Julien Stroumza
- The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA
| | - Claire Dugast-Darzacq
- Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of California, Berkeley, CA, 94720, USA
| | - Thomas G W Graham
- Department of Molecular and Cell Biology, Division of Genetics, Genomics and Development, University of California, Berkeley, CA, 94720, USA
| | - Xuanting Wang
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA
| | - Steffen Jockusch
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA
- Department of Chemistry, Columbia University, New York, NY, 10027, USA
| | - Chuanjuan Tao
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA
| | - Minchen Chien
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA
| | - Wei Xie
- Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA
| | - Dinshaw J Patel
- Laboratory of Structural Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA
| | - Cindy Meyer
- Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA
| | - Aitor Garzia
- Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA
| | - Thomas Tuschl
- Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, 10065, USA
| | - James J Russo
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA
| | - Jingyue Ju
- Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY, 10027, USA
- Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, 10032, USA
| | - Anders M Näär
- Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA, 94720, USA
- Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA
| | - Sarah Stanley
- Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA.
- Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, 94720, USA.
| | - Julia Schaletzky
- The Henry Wheeler Center for Emerging and Neglected Diseases, 344 Li Ka Shing, Berkeley, CA, 94720, USA.
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13
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Karunakaran KB, Balakrishnan N, Ganapathiraju MK. Interactome of SARS-CoV-2 Modulated Host Proteins With Computationally Predicted PPIs: Insights From Translational Systems Biology Studies. FRONTIERS IN SYSTEMS BIOLOGY 2022; 2. [DOI: 10.3389/fsysb.2022.815237] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Accelerated efforts to identify intervention strategies for the COVID-19 pandemic caused by SARS-CoV-2 need to be supported by deeper investigations into host invasion and response mechanisms. We constructed the neighborhood interactome network of the 332 human proteins targeted by SARS-CoV-2 proteins, augmenting it with 1,941 novel human protein-protein interactions predicted using our High-precision Protein-Protein Interaction Prediction (HiPPIP) model. Novel interactors, and the interactome as a whole, showed significant enrichment for genes differentially expressed in SARS-CoV-2-infected A549 and Calu-3 cells, postmortem lung samples of COVID-19 patients and blood samples of COVID-19 patients with severe clinical outcomes. The PPIs connected host proteins to COVID-19 blood biomarkers, ACE2 (SARS-CoV-2 entry receptor), genes differentiating SARS-CoV-2 infection from other respiratory virus infections, and SARS-CoV-targeted host proteins. Novel PPIs facilitated identification of the cilium organization functional module; we deduced the potential antiviral role of an interaction between the virus-targeted NUP98 and the cilia-associated CHMP5. Functional enrichment analyses revealed promyelocytic leukaemia bodies, midbody, cell cycle checkpoints and tristetraprolin pathway as potential viral targets. Network proximity of diabetes and hypertension associated genes to host proteins indicated a mechanistic basis for these co-morbidities in critically ill/non-surviving patients. Twenty-four drugs were identified using comparative transcriptome analysis, which include those undergoing COVID-19 clinical trials, showing broad-spectrum antiviral properties or proven activity against SARS-CoV-2 or SARS-CoV/MERS-CoV in cell-based assays. The interactome is available on a webserver at http://severus.dbmi.pitt.edu/corona/.
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14
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Gunaratne GS, Marchant JS. The ins and outs of virus trafficking through acidic Ca 2+ stores. Cell Calcium 2022; 102:102528. [PMID: 35033909 PMCID: PMC8860173 DOI: 10.1016/j.ceca.2022.102528] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 12/20/2022]
Abstract
Many viruses exploit host-cell Ca2+ signaling processes throughout their life cycle. This is especially relevant for viruses that translocate through the endolysosomal system, where cellular infection is keyed to the microenvironment of these acidic Ca2+ stores and Ca2+-dependent trafficking pathways. As regulators of the endolysosomal ionic milieu and trafficking dynamics, two families of endolysosomal Ca2+-permeable cation channels - two pore channels (TPCs) and transient receptor potential mucolipins (TRPMLs) - have emerged as important host-cell factors in viral entry. Here, we review: (i) current evidence implicating Ca2+ signaling in viral translocation through the endolysosomal system, (ii) the roles of these ion channels in supporting cellular infection by different viruses, and (iii) areas for future research that will help define the potential of TPC and TRPML ligands as progressible antiviral agents.
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Affiliation(s)
- Gihan S Gunaratne
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA.
| | - Jonathan S Marchant
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee WI 53226, USA
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15
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Berlansky S, Sallinger M, Grabmayr H, Humer C, Bernhard A, Fahrner M, Frischauf I. Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies. Cells 2022; 11:253. [PMID: 35053369 PMCID: PMC8773957 DOI: 10.3390/cells11020253] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 01/05/2022] [Accepted: 01/11/2022] [Indexed: 01/09/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). This respiratory illness was declared a pandemic by the world health organization (WHO) in March 2020, just a few weeks after being described for the first time. Since then, global research effort has considerably increased humanity's knowledge about both viruses and disease. It has also spawned several vaccines that have proven to be key tools in attenuating the spread of the pandemic and severity of COVID-19. However, with vaccine-related skepticism being on the rise, as well as breakthrough infections in the vaccinated population and the threat of a complete immune escape variant, alternative strategies in the fight against SARS-CoV-2 are urgently required. Calcium signals have long been known to play an essential role in infection with diverse viruses and thus constitute a promising avenue for further research on therapeutic strategies. In this review, we introduce the pivotal role of calcium signaling in viral infection cascades. Based on this, we discuss prospective calcium-related treatment targets and strategies for the cure of COVID-19 that exploit viral dependence on calcium signals.
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Affiliation(s)
| | | | | | | | | | - Marc Fahrner
- Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria; (S.B.); (M.S.); (H.G.); (C.H.); (A.B.)
| | - Irene Frischauf
- Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria; (S.B.); (M.S.); (H.G.); (C.H.); (A.B.)
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16
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Bergantin LB. A Timeline of Ca 2+/cAMP Signalling: From Basic Research to Potential Therapeutics for Dementia. Curr Alzheimer Res 2022; 19:179-187. [PMID: 35430979 DOI: 10.2174/1567205019666220415125447] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/12/2022] [Accepted: 03/06/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND The hypothesis that a dyshomeostasis of Ca2+ increases the incidence of dementia has been established. Several discoveries have emphasized the concept that a decrease in the excess of Ca2+ could be an interesting pharmacological target to alleviate dementia symptoms. Aging along with a healthy brain can be supported by daily exercise, self-control in caloric ingestion, and participation in intellectually challenging events. These lifestyle factors may alleviate the excess of Ca2+ resulting from a Ca2+ dyshomeostasis. Curiously, epidemiological and clinical studies have also reported a clinical relationship between hypertension, diabetes, and other inflammatory processes, and a higher risk of cognition decline. Considering the cumulative data from the scientific literature, including data of high evidence such as meta-analysis and systematic reviews, we can now link a Ca2+ dyshomeostasis as an upstream factor for hypertension, diabetes and other inflammatory processes, and dementia. Several reports have also indicated that increasing cAMP levels may induce neuroprotective outcomes, thus alleviating dementia symptoms. METHODS With these concepts in mind, we found that the pharmacological manipulation of Ca2+/cAMP signalling could be a novel plausible target to treat dementia. This article puts together fundamental concepts and current therapies to treat dementia, including novel therapeutics coming from the pharmacological manipulation of Ca2+/cAMP signalling. RESULTS Then, combined with improvements in the lifestyle issues, these novel therapeutics may allow sustained improvements in the life quality of age-related neurological patients. CONCLUSIONS In addition, considering coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviewed recent reports about Ca2+ channel blockers' role in restoring Ca2+ signalling disruption due to COVID-19. Finally, this article also presents a timeline of the major events in Ca2+/cAMP signaling.
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Affiliation(s)
- Leandro B Bergantin
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, Vila Clementino, São Paulo, SP, Postal Code: 04039-032, Brazil
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17
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Bergantin LB. Mental Disorders and Poor COVID-19 Prognosis: Reevaluating the Relationship through Ca 2+/cAMP Signalling. Curr Top Med Chem 2022; 22:1215-1218. [PMID: 35524666 DOI: 10.2174/1568026622666220504163811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 03/12/2022] [Accepted: 03/18/2022] [Indexed: 11/22/2022]
Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, Vila Clementino, São Paulo, SP, Brazil
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18
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Bergantin LB. The Interactions among Hypertension, Cancer, and COVID-19: Perspective with Regard to Ca 2+/cAMP Signalling. Curr Cancer Drug Targets 2022; 22:351-360. [PMID: 35168520 DOI: 10.2174/1568009622666220215143805] [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: 09/09/2021] [Revised: 12/02/2021] [Accepted: 12/16/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The hypothesis that hypertension is clinically associated with an enhanced risk of developing cancer has been highlighted. However, the working principles involved in this link are still under intensive discussion. A correlation among inflammation, hypertension, and cancer could accurately describe the clinical link between these diseases. In addition, dyshomeostasis of Ca2+ has been considered to be involved in both cancer and hypertension, and inflammation. There is a strong link between Ca2+ signalling, e.g. enhanced Ca2+ signals, and inflammatory outcomes. cAMP also modulates pro- and anti-inflammatory outcomes; pharmaceuticals, which increase intracellular cAMP levels, can decrease the production of proinflammatory mediators and enhance the production of antiinflammatory outcomes. OBJECTIVE This article highlights the participation of Ca2+/cAMP signalling in the clinical association among inflammation, hypertension, and an enhanced risk for the development of cancer. In addition, considering that research on coronavirus disease 2019 (COVID-19) is a rapidly evolving field, this article also reviews recent reports related to the role of Ca2+ channel blockers in restoring Ca2+ signalling disruption due to COVID-19, including the relationship among COVID-19, cancer, and hypertension. CONCLUSION An understanding of the association among these diseases could expand current pharmacotherapy, involving Ca2+ channel blockers and pharmaceuticals that facilitate a rise in cAMP levels.
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Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Laboratory of Autonomic and Cardiovascular Pharmacology, 55 11 5576-4973, Rua Pedro de Toledo, 669, Vila Clementino, São Paulo, SP, Brazil
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19
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Bergantin LB. Neuroinflammation, Diabetes and COVID-19: Perspectives Coming from Ca 2+/cAMP Signalling. Curr Drug Res Rev 2022; 14:6-10. [PMID: 34970961 DOI: 10.2174/2589977514666211231141401] [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: 08/21/2021] [Revised: 10/15/2021] [Accepted: 11/06/2021] [Indexed: 12/15/2022]
Abstract
A link between inflammatory diseases, e.g., epilepsy, dementia, diabetes, and COVID-19, has been established. For instance, observational studies involving several individuals reported that people with epilepsy show an enhanced incidence of manifesting dysfunctions related to cognition, e.g., dementia, while people with dementia have a higher incidence of manifesting epilepsy, thus an evident bidirectional relationship between epilepsy and dementia might occur. In addition, epilepsy commonly cooccurs in patients with diabetes, indicating an association between these two disorders. Intriguingly, some reports have also observed a poor prognosis of people with both diabetes and COVID-19. It is recognized that a dyshomeostasis of both Ca2+ and cAMP signalling pathways could be a molecular connection for these disorders. Therefore, clarifying this clinical relationship among epilepsy, dementia, diabetes, and COVID-19 may outcome in novel hypotheses for identifying the etiology of these disorders.
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Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo - Rua Pedro de Toledo, 669 - Vila Clementino, São Paulo - SP 04039-032, Brazil
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20
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Bergantin LB. COVID-19 and Obesity: Reevaluating the Relationship Through Ca 2+/cAMP Signalling. Curr Drug Res Rev 2022; 14:157-159. [PMID: 36281829 DOI: 10.2174/1573399818666220429100819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/19/2022] [Accepted: 03/14/2022] [Indexed: 06/16/2023]
Affiliation(s)
- Leandro Bueno Bergantin
- Department of Pharmacology - Escola Paulista de Medicina - Universidade Federal de São Paulo - Rua Pedro de Toledo, 669 - Vila Clementino, São Paulo - SP, Brazil, 04039-032
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21
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Rodriguez-Rodriguez BA, Noval MG, Kaczmarek ME, Jang KK, Thannickal SA, Cifuentes Kottkamp A, Brown RS, Kielian M, Cadwell K, Stapleford KA. Atovaquone and Berberine Chloride Reduce SARS-CoV-2 Replication In Vitro. Viruses 2021; 13:v13122437. [PMID: 34960706 PMCID: PMC8706021 DOI: 10.3390/v13122437] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/24/2021] [Accepted: 12/01/2021] [Indexed: 01/05/2023] Open
Abstract
Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits.
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Affiliation(s)
- Bruno A. Rodriguez-Rodriguez
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
| | - Maria G. Noval
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
| | - Maria E. Kaczmarek
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
| | - Kyung Ku Jang
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Sara A. Thannickal
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
| | | | - Rebecca S. Brown
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (R.S.B.); (M.K.)
| | - Margaret Kielian
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (R.S.B.); (M.K.)
| | - Ken Cadwell
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY 10016, USA
- Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA;
| | - Kenneth A. Stapleford
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; (B.A.R.-R.); (M.G.N.); (M.E.K.); (K.K.J.); (S.A.T.); (K.C.)
- Correspondence:
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22
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Straus MR, Bidon MK, Tang T, Jaimes JA, Whittaker GR, Daniel S. Inhibitors of L-Type Calcium Channels Show Therapeutic Potential for Treating SARS-CoV-2 Infections by Preventing Virus Entry and Spread. ACS Infect Dis 2021; 7:2807-2815. [PMID: 34498840 PMCID: PMC8442615 DOI: 10.1021/acsinfecdis.1c00023] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Indexed: 01/06/2023]
Abstract
COVID-19 is caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus (CoV)-2 (SARS-CoV-2). The virus is responsible for an ongoing pandemic and concomitant public health crisis around the world. While vaccine development is proving to be highly successful, parallel drug development approaches are also critical in the response to SARS-CoV-2 and other emerging viruses. Coronaviruses require Ca2+ ions for host cell entry, and we have previously shown that Ca2+ modulates the interaction of the viral fusion peptide with host cell membranes. In an attempt to accelerate drug repurposing, we tested a panel of L-type calcium channel blocker (CCB) drugs currently developed for other conditions to determine whether they would inhibit SARS-CoV-2 infection in cell culture. All the CCBs tested showed varying degrees of inhibition, with felodipine and nifedipine strongly limiting SARS-CoV-2 entry and infection in epithelial lung cells at concentrations where cell toxicity was minimal. Further studies with pseudotyped particles displaying the SARS-CoV-2 spike protein suggested that inhibition occurs at the level of virus entry. Overall, our data suggest that certain CCBs have the potential to treat SARS-CoV-2 infections and are worthy of further examination for possible treatment of COVID-19.
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Affiliation(s)
- Marco R. Straus
- Department of Microbiology & Immunology, College
of Veterinary Medicine, Cornell University, Ithaca, New York
14853, United States
| | - Miya K. Bidon
- Robert Frederick Smith School of Chemical &
Biomolecular Engineering, Cornell University, Ithaca, New York
14853, United States
| | - Tiffany Tang
- Robert Frederick Smith School of Chemical &
Biomolecular Engineering, Cornell University, Ithaca, New York
14853, United States
| | - Javier A. Jaimes
- Department of Microbiology & Immunology, College
of Veterinary Medicine, Cornell University, Ithaca, New York
14853, United States
| | - Gary R. Whittaker
- Department of Microbiology & Immunology, College
of Veterinary Medicine, Cornell University, Ithaca, New York
14853, United States
- Master of Public Health Program, Cornell
University, Ithaca, New York 14853, United States
| | - Susan Daniel
- Robert Frederick Smith School of Chemical &
Biomolecular Engineering, Cornell University, Ithaca, New York
14853, United States
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23
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Saurav S, Tanwar J, Ahuja K, Motiani RK. Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance. Mol Aspects Med 2021; 81:101004. [PMID: 34304899 PMCID: PMC8299155 DOI: 10.1016/j.mam.2021.101004] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/18/2021] [Accepted: 07/16/2021] [Indexed: 12/22/2022]
Abstract
Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca2+) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca2+ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca2+ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca2+ homeostasis. The focus of this review is to first discuss the role of host cell Ca2+ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca2+ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca2+ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca2+ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca2+ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.
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Affiliation(s)
- Suman Saurav
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Jyoti Tanwar
- CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi-110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Kriti Ahuja
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Rajender K Motiani
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India.
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24
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Zhao F, Yang Z, Wang N, Jin K, Luo Y. Traditional Chinese Medicine and Western Medicine Share Similar Philosophical Approaches to Fight COVID-19. Aging Dis 2021; 12:1162-1168. [PMID: 34341699 PMCID: PMC8279530 DOI: 10.14336/ad.2021.0512] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/12/2021] [Indexed: 12/24/2022] Open
Abstract
Though disciplines in the same field, modern medicine (Western medicine) and traditional medicine (Traditional Chinese medicine, TCM) have been viewed as two distinct and divergent fields of medicine and thus differ greatly in their ways of diagnosing, treating, and preventing disease. In brief, Western medicine is primarily an evidence (laboratory)-based science, whereas TCM is more of a healing art based on the theory of Yin and Yang and the five elements in the human body. Therefore, whether TCM and Western medicine could use similar philosophical approaches to treat disease remains unclear. It is well-known that vitamin D enhances immune function and reduces the spread of some viruses. Indeed, recent evidence shows that the blood calcium level is strongly associated with COVID-19 severity, and vitamin D supplementation has shown favorable effects in viral infections. According to TCM theory, the pathogenesis of COVID-19 is closely associated with cold-dampness, an etiological factor in TCM. Cold-dampness could be attenuated by sun exposure and Wenyang herbs, both of which can restore the vitamin D level in the blood in Western medicine. Therefore, TCM and Western medicine could share similar philosophical methods to fight COVID-19 and understanding their philosophical theories could achieve the maximum benefits for treatment of COVID-19 and other diseases.
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Affiliation(s)
- Fangfang Zhao
- 1Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Zhenhong Yang
- 1Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Ningqun Wang
- 1Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Kunlin Jin
- 2Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, TX 76107, USA
| | - Yumin Luo
- 1Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China.,3 Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
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25
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Peng C, Wang H, Guo YF, Qi GY, Zhang CX, Chen T, He J, Jin ZC. Calcium channel blockers improve prognosis of patients with coronavirus disease 2019 and hypertension. Chin Med J (Engl) 2021; 134:1602-1609. [PMID: 34133354 PMCID: PMC8280095 DOI: 10.1097/cm9.0000000000001479] [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: 11/22/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Hypertension is considered an important risk factor for the coronavirus disease 2019 (COVID-19). The commonly anti-hypertensive drugs are the renin-angiotensin-aldosterone system (RAAS) inhibitors, calcium channel blockers (CCBs), and beta-blockers. The association between commonly used anti-hypertensive medications and the clinical outcome of COVID-19 patients with hypertension has not been well studied. METHODS We conducted a retrospective cohort study that included all patients admitted with COVID-19 to Huo Shen Shan Hospital and Guanggu District of the Maternal and Child Health Hospital of Hubei Province, Wuhan, China. Clinical and laboratory characteristics were extracted from electronic medical records. Hypertension and anti-hypertensive treatment were confirmed by medical history and clinical records. The primary clinical endpoint was all-cause mortality. Secondary endpoints included the rates of patients in common wards transferred to the intensive care unit and hospital stay duration. Logistic regression was used to explore the risk factors associated with mortality and prognosis. Propensity score matching was used to balance the confounders between different anti-hypertensive treatments. Kaplan-Meier curves were used to compare the cumulative recovery rate. Log-rank tests were performed to test for differences in Kaplan-Meier curves between different groups. RESULTS Among 4569 hospitalized patients with COVID-19, 31.7% (1449/4569) had a history of hypertension. There were significant differences in mortality rates between hypertensive patients with CCBs (7/359) and those without (21/359) (1.95% vs. 5.85%, risk ratio [RR]: 0.32, 95% confidence interval [CI]: 0.13-0.76, χ2 = 7.61, P = 0.0058). After matching for confounders, the mortality rates were similar between the RAAS inhibitor (4/236) and non-RAAS inhibitor (9/236) cohorts (1.69% vs. 3.81%, RR: 0.43, 95% CI: 0.13-1.43, χ2 = 1.98, P = 0.1596). Hypertensive patients with beta-blockers (13/340) showed no statistical difference in mortality compared with those without (11/340) (3.82% vs. 3.24%, RR: 1.19, 95% CI: 0.53-2.69, χ2 = 0.17, P = 0.6777). CONCLUSIONS In our study, we did not find any positive or negative effects of RAAS inhibitors or beta-blockers in COVID-19 patients with hypertension, while CCBs could improve prognosis.
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Affiliation(s)
- Chi Peng
- Department of Health Statistics, Naval Medical University, Shanghai 200433, China
| | - Hao Wang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yu-Feng Guo
- Department of Medical Administration, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Ge-Yao Qi
- Department of Health Statistics, Naval Medical University, Shanghai 200433, China
| | - Chen-Xu Zhang
- Department of Health Statistics, Naval Medical University, Shanghai 200433, China
| | - Ting Chen
- Department of Cardiology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia He
- Department of Health Statistics, Naval Medical University, Shanghai 200433, China
| | - Zhi-Chao Jin
- Department of Health Statistics, Naval Medical University, Shanghai 200433, China
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Choksi TT, Zhang H, Chen T, Malhotra N. Outcomes of Hospitalized COVID-19 Patients Receiving Renin Angiotensin System Blockers and Calcium Channel Blockers. Am J Nephrol 2021; 52:250-260. [PMID: 33827074 PMCID: PMC8089461 DOI: 10.1159/000515232] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/10/2021] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Use of certain antihypertensive medications has been an area of interest during the COVID-19 pandemic, and several hypotheses have been developed regarding the effects of renin-angiotensin system blockers as well as calcium channel blockers in those infected with COVID-19. We seek to determine the association between exposure to ACEI, ARB, and CCB and outcomes in those admitted to the hospital with COVID-19 infection. METHODS This retrospective cohort study included 841 adult patients hospitalized with COVID-19 infection at the University of Chicago Medical Center between March 25 and June 22, 2020. Out of these 841, 453 patients had a personal history of hypertension. For the first part, we evaluated primary outcomes of in-hospital mortality and ICU admission in hospitalized COVID-19 patients based on their exposure to particular medications regardless of a personal history of hypertension and compared them with those who were not on these medications. For the second part, we evaluated the aforementioned outcomes in 453 patients with a personal history of hypertension based on their medication exposure. Secondary outcomes of length of stay, readmission rate, and new-onset dialysis requirement were also compared across the study groups. RESULTS Out of 841 patients, 111 (13.19%) were on ACEI/ARB (median age: 66.1, SD 15.4; 52.25% females) and 730 (86.80%) were not on them (median age: 56.6, SD 20.3; 50.14% females), while 277 (32.93%) used CCB (median age: 64.6, SD 15.2; 57.04% females) and 564 (67.06%) did not use CCB (median age: 54.6, SD 21.2; 47.16% females). After adjusting for demographics and covariates, neither ACEI/ARB nor CCB exposure was associated with any effect on mortality, but ACEI/ARB exposure was associated with 42% reduction in risk of ICU admissions (OR 0.58, 95% CI [0.35, 0.95], p value 0.03). In addition, combined use of ACEI/ARB and CCB was associated with statistically significant (45%) reduction in ICU admission (OR 0.55, 95% CI [0.32, 0.94], p value 0.029). Out of 453 patients with a personal history of hypertension, 85 (18.76%) were taking ACEI/ARB (median age 65, SD 15.6; 56.47% females) and 368 (81.24%) were not on ACEI/ARB (median age 62.8, SD 16.4; 54.89% females), while 208 (45.92%) out of 453 were on CCB (median age 65; SD 14.8; 60.1% females) and 245 (54.08%) were not on CCB (median age 61.7, SD 17.3; 51.02% females). In the fully adjusted model in this group, ACEI use was associated with 71% reduction in in-house mortality (OR 0.29, 95% CI [0.09, 0.93], p value 0.03). DISCUSSION/CONCLUSION Among all hospitalized patients with COVID-19 infection, exposure to ACEI/ARB, as well as combined exposure to ACEI/ARB and CCB, were associated with reduced incidence of ICU admissions. In those admitted patients who had a personal history of hypertension, there was a trend towards reduced in-hospital mortality in those exposed to ACEI.
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Affiliation(s)
- Tatvam T. Choksi
- Department of Hospital Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA
- * Tatvam Choksi,
| | - Hui Zhang
- The Center for Health and the Social Sciences, The University of Chicago, Chicago, Illinois, USA
| | - Thomas Chen
- Department of Hospital Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA
| | - Nikhil Malhotra
- Department of Hospital Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA
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Bao MN, Zhang LJ, Tang B, Fu DD, Li J, Du L, Hou YN, Zhang ZL, Tang HW, Pang DW. Influenza A Viruses Enter Host Cells via Extracellular Ca2+ Influx-Involved Clathrin-Mediated Endocytosis. ACS APPLIED BIO MATERIALS 2021; 4:2044-2051. [DOI: 10.1021/acsabm.0c00968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Meng-Ni Bao
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Li-Juan Zhang
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Bo Tang
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Dan-Dan Fu
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Jing Li
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Lei Du
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Yi-Ning Hou
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Zhi-Ling Zhang
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Hong-Wu Tang
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
| | - Dai-Wen Pang
- College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, and The Institute for Advanced Studies, Wuhan University, Wuhan 430072, P. R. China
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, and College of Chemistry, Nankai University, Tianjin 300071, P. R. China
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Krishnamoorthy P, Raj AS, Roy S, Kumar NS, Kumar H. Comparative transcriptome analysis of SARS-CoV, MERS-CoV, and SARS-CoV-2 to identify potential pathways for drug repurposing. Comput Biol Med 2021; 128:104123. [PMID: 33260034 PMCID: PMC7683955 DOI: 10.1016/j.compbiomed.2020.104123] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 12/15/2022]
Abstract
The ongoing COVID-19 pandemic caused by the coronavirus, SARS-CoV-2, has already caused in excess of 1.25 million deaths worldwide, and the number is increasing. Knowledge of the host transcriptional response against this virus and how the pathways are activated or suppressed compared to other human coronaviruses (SARS-CoV, MERS-CoV) that caused outbreaks previously can help in the identification of potential drugs for the treatment of COVID-19. Hence, we used time point meta-analysis to investigate available SARS-CoV and MERS-CoV in-vitro transcriptome datasets in order to identify the significant genes and pathways that are dysregulated at each time point. The subsequent over-representation analysis (ORA) revealed that several pathways are significantly dysregulated at each time point after both SARS-CoV and MERS-CoV infection. We also performed gene set enrichment analyses of SARS-CoV and MERS-CoV with that of SARS-CoV-2 at the same time point and cell line, the results of which revealed that common pathways are activated and suppressed in all three coronaviruses. Furthermore, an analysis of an in-vivo transcriptomic dataset of COVID-19 patients showed that similar pathways are enriched to those identified in the earlier analyses. Based on these findings, a drug repurposing analysis was performed to identify potential drug candidates for combating COVID-19.
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Affiliation(s)
- Pandikannan Krishnamoorthy
- Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, 462066, MP, India
| | - Athira S Raj
- Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, 462066, MP, India
| | - Swagnik Roy
- Microbiology Department, Zoram Medical College, Falkawn, Mizoram, 796005, India
| | | | - Himanshu Kumar
- Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal, 462066, MP, India; Laboratory of Host Defense, WPI Immunology, Frontier Research Centre, Osaka University, Osaka, 5650871, Japan.
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Crespi B, Alcock J. Conflicts over calcium and the treatment of COVID-19. EVOLUTION MEDICINE AND PUBLIC HEALTH 2020; 9:149-156. [PMID: 33732462 PMCID: PMC7717197 DOI: 10.1093/emph/eoaa046] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/03/2020] [Indexed: 12/15/2022]
Abstract
Several recent studies have provided evidence that use of calcium channel blockers (CCBs), especially amlodipine and nifedipine, can reduce mortality from coronavirus disease 2019 (COVID-19). Moreover, hypocalcemia (a reduced level of serum ionized calcium) has been shown to be strongly positively associated with COVID-19 severity. Both effectiveness of CCBs as antiviral therapy, and positive associations of hypocalcemia with mortality, have been demonstrated for many other viruses as well. We evaluate these findings in the contexts of virus–host evolutionary conflicts over calcium metabolism, and hypocalcemia as either pathology, viral manipulation or host defence against pathogens. Considerable evidence supports the hypothesis that hypocalcemia represents a host defence. Indeed, hypocalcemia may exert antiviral effects in a similar manner as do CCBs, through interference with calcium metabolism in virus-infected cells. Prospective clinical studies that address the efficacy of CCBs and hypocalcemia should provide novel insights into the pathogenicity and treatment of COVID-19 and other viruses.
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Affiliation(s)
- Bernard Crespi
- Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada
| | - Joe Alcock
- Department of Emergency Medicine, University of New Mexico, Albuquerque, NM, USA
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Vela JM. Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy? Front Pharmacol 2020; 11:582310. [PMID: 33364957 PMCID: PMC7751758 DOI: 10.3389/fphar.2020.582310] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Accepted: 09/30/2020] [Indexed: 12/27/2022] Open
Abstract
Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.
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Affiliation(s)
- José Miguel Vela
- Drug Discovery and Preclinical Development, ESTEVE Pharmaceuticals, Barcelona, Spain
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31
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Karunakaran KB, Balakrishnan N, Ganapathiraju M. Potentially repurposable drugs for COVID-19 identified from SARS-CoV-2 Host Protein Interactome. RESEARCH SQUARE 2020:rs.3.rs-30363. [PMID: 32702734 PMCID: PMC7336709 DOI: 10.21203/rs.3.rs-30363/v1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We previously presented the protein-protein interaction network - the 'HoP' or the host protein interactome - of 332 host proteins that were identified to interact with 27 nCoV19 viral proteins by Gordon et al. Here, we studied drugs targeting the proteins in this interactome to identify whether any of them may potentially be repurposable against SARS-CoV-2. We studied each of the drugs using the BaseSpace Correlation Engine and identified those that induce gene expression profiles negatively correlated with SARS-associated expression profile. This analysis resulted in 20 drugs whose differential gene expression (drug versus normal) had an anti-correlation with differential expression for SARS (viral infection versus normal). These included drugs that were already being tested for their clinical activity against SARS-CoV-2, those with proven activity against SARS-CoV/MERS-CoV, broad-spectrum antiviral drugs, and those identified/prioritized by other computational re-purposing studies. In summary, our integrated computational analysis of the HoP interactome in conjunction with drug-induced transcriptomic data resulted in drugs that may be repurposable for COVID-19.
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Abstract
Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular "kinome," have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.
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Host Calcium Channels and Pumps in Viral Infections. Cells 2019; 9:cells9010094. [PMID: 31905994 PMCID: PMC7016755 DOI: 10.3390/cells9010094] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 12/23/2019] [Accepted: 12/24/2019] [Indexed: 11/29/2022] Open
Abstract
Ca2+ is essential for virus entry, viral gene replication, virion maturation, and release. The alteration of host cells Ca2+ homeostasis is one of the strategies that viruses use to modulate host cells signal transduction mechanisms in their favor. Host calcium-permeable channels and pumps (including voltage-gated calcium channels, store-operated channels, receptor-operated channels, transient receptor potential ion channels, and Ca2+-ATPase) mediate Ca2+ across the plasma membrane or subcellular organelles, modulating intracellular free Ca2+. Therefore, these Ca2+ channels or pumps present important aspects of viral pathogenesis and virus–host interaction. It has been reported that viruses hijack host calcium channels or pumps, disturbing the cellular homeostatic balance of Ca2+. Such a disturbance benefits virus lifecycles while inducing host cells’ morbidity. Evidence has emerged that pharmacologically targeting the calcium channel or calcium release from the endoplasmic reticulum (ER) can obstruct virus lifecycles. Impeding virus-induced abnormal intracellular Ca2+ homeostasis is becoming a useful strategy in the development of potent antiviral drugs. In this present review, the recent identified cellular calcium channels and pumps as targets for virus attack are emphasized.
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The Interferon-Inducible Proteoglycan Testican-2/SPOCK2 Functions as a Protective Barrier against Virus Infection of Lung Epithelial Cells. J Virol 2019; 93:JVI.00662-19. [PMID: 31341044 DOI: 10.1128/jvi.00662-19] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023] Open
Abstract
Proteoglycans function not only as structural components of the extracellular compartment but also as regulators of various cellular events, including cell migration, inflammation, and infection. Many microbial pathogens utilize proteoglycans to facilitate adhesion and invasion into host cells. Here we report a secreted form of a novel heparan sulfate proteoglycan that functions against virus infection. The expression of SPOCK2/testican-2 was significantly induced in virus-infected lungs or in interferon (IFN)-treated alveolar lung epithelial cells. Overexpression from a SPOCK2 expression plasmid alone or the treatment of cells with recombinant SPOCK2 protein efficiently blocked influenza virus infection at the step of viral attachment to the host cell and entry. Moreover, mice treated with purified SPOCK2 were protected against virus infection. Sialylated glycans and heparan sulfate chains covalently attached to the SPOCK2 core protein were critical for its antiviral activity. Neuraminidase (NA) of influenza virus cleaves the sialylated moiety of SPOCK2, thereby blocking its binding to the virus. Our data suggest that IFN-induced SPOCK2 functions as a decoy receptor to bind and block influenza virus infection, thereby restricting entry of the infecting virus into neighboring cells.IMPORTANCE Here we report a novel proteoglycan protein, testican-2/SPOCK2, that prevents influenza virus infection. Testican-2/SPOCK2 is a complex type of secreted proteoglycan with heparan sulfate GAG chains attached to the core protein. SPOCK2 expression is induced upon virus infection or by interferons, and the protein is secreted to an extracellular compartment, where it acts directly to block virus-cell attachment and entry. Treatment with purified testican-2/SPOCK2 protein can efficiently block influenza virus infection in vitro and in vivo We also identified the heparan sulfate moiety as a key regulatory module for this inhibitory effect. Based on its mode of action (cell attachment/entry blocker) and site of action (extracellular compartment), we propose testican-2/SPOCK2 as a potential antiviral agent that can efficiently control influenza virus infection.
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Lima WG, Ramos-Alves MC, Soares AC. Dos distúrbios psiquiátricos à antibioticoterapia: reposicionamento da clorpromazina como agente antibacteriano. ACTA ACUST UNITED AC 2019. [DOI: 10.15446/rcciquifa.v48n1.80062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
O alarmante aumento na taxa de resistência aos antibióticos põe em check à eficácia da terapia antibacteriana futura. Em contrapartida, as indústrias farmacêuticas negligenciam os investimentos em pesquisa e desenvolvimento de novos fármacos antimicrobianos em virtude de questões financeiras, legais e farmacológicas. Assim sendo, o reposicionamento de agentes disponíveis clinicamente torna-se uma promissora ferramenta para tentar driblar o desinteresse das indústrias. O fármaco antipsicótico clorpromazina (CPZ) destaca-se por possuir uma ampla faixa de atividade antibacteriana, a qual cobre desde patógenos Gram-positivos e Gram-negativos, até as micobactérias. A atividade antibacteriana é independente do perfil de susceptibilidade do microrganismo, sendo ela mantida mesmo em cepas altamente resistentes aos antibióticos. Alguns estudos mostram que mesmo nas concentrações clinicamente disponíveis no plasma (entre 0,1-0,5 μg/mL), a CPZ é capaz de matar Staphylococcus aureus e Mycobacterium tuberculosis dentro dos macrófagos. Em adição, estudos clínicos têm revelado os benefícios do uso da CPZ na terapia de suporte para pacientes com infecções em curso. Em conclusão, a CPZ pode eventualmente ser direcionada ao arsenal terapêutico antimicrobiano, especialmente no manejo das infecções causadas por microrganismos intracelulares com fenótipo multirresistente.
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Hoffmann M, Pöhlmann S. Cell Entry of Influenza A Viruses: Sweet Talk between HA and Ca V1.2. Cell Host Microbe 2018; 23:697-699. [PMID: 29902433 DOI: 10.1016/j.chom.2018.05.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Influenza A viruses attach to sialic acids on host cells. In this issue of Cell Host & Microbe, Fujioka et al. (2018) show that binding to a specific sialylated cellular protein facilitates infection: engagement of sialic acids linked to the Ca2+ channel CaV1.2 induces Ca2+ oscillations, which promote infectious entry.
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Affiliation(s)
- Markus Hoffmann
- Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center, 37077 Göttingen, Germany.
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A Sialylated Voltage-Dependent Ca 2+ Channel Binds Hemagglutinin and Mediates Influenza A Virus Entry into Mammalian Cells. Cell Host Microbe 2018; 23:809-818.e5. [PMID: 29779930 DOI: 10.1016/j.chom.2018.04.015] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 04/04/2018] [Accepted: 04/23/2018] [Indexed: 12/19/2022]
Abstract
Influenza A virus (IAV) infection is initiated by the attachment of the viral glycoprotein hemagglutinin (HA) to sialic acid on the host cell surface. However, the sialic acid-containing receptor crucial for IAV infection has remained unidentified. Here, we show that HA binds to the voltage-dependent Ca2+ channel Cav1.2 to trigger intracellular Ca2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca2+ channel blockers (CCBs) or by knockdown of Cav1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of Cav1.2 restored Ca2+ oscillations and virus infection in Cav1.2-depleted cells, demonstrating the significance of Cav1.2 sialylation. Taken together, we identify Cav1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry.
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Zhang S, Wu Y, Xuan Z, Chen X, Zhang J, Ge D, Wang X. Screening differential miRNAs responsible for permeability increase in HUVECs infected with influenza A virus. PLoS One 2017; 12:e0186477. [PMID: 29059211 PMCID: PMC5653366 DOI: 10.1371/journal.pone.0186477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 10/01/2017] [Indexed: 11/24/2022] Open
Abstract
Severe influenza infections are featured by acute lung injury, a syndrome of increased pulmonary microvascular permeability. A growing number of evidences have shown that influenza A virus induces cytoskeletal rearrangement and permeability increase in endothelial cells. Although miRNA’s involvement in the regulation of influenza virus infection and endothelial cell (EC) function has been well documented, little is known about the miRNA profiles in influenza-infected endothelial cells. Using human umbilical vein endothelial cells (HUVECs) as cell models, the present study aims to explore the differential miRNAs in influenza virus-infected ECs and analyze their target genes involved in EC permeability regulation. As the results showed, permeability increased and F-actin cytoskeleton reorganized after HUVECs infected with influenza A virus (CA07 or PR8) at 30 MOI. MicroRNA microarray revealed a multitude of miRNAs differentially expressed in HUVECs after influenza virus infection. Through target gene prediction, we found that a series of miRNAs were involved in PKC, Rho/ROCK, HRas/Raf/MEK/ERK, and Ca2+/CaM pathways associated with permeability regulation, and most of these miRNAs were down-regulated after flu infection. It has been reported that PKC, Rho/ROCK, HRas/Raf/MEK/ERK, and Ca2+/CaM pathways are activated by flu infection and play important roles in permeability regulation. Therefore, the cumulative effects of these down-regulated miRNAs which synergistically enhanced activation of PKC, Rho/ROCK, Ras/Raf/MEK/ERK, and Ca2+/CaM pathways, can eventually lead to actin rearrangement and hyperpermeability in flu-infected HUVECs.
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Affiliation(s)
- Shujing Zhang
- Scientific Research Center, Beijing University of Chinese Medicine, Beijing, China
| | - Ying Wu
- Department of Microbiology and Immunology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
- * E-mail:
| | - Zinan Xuan
- Department of Microbiology and Immunology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoming Chen
- Department of Microbiology and Immunology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Junjie Zhang
- Department of Microbiology and Immunology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Dongyu Ge
- Scientific Research Center, Beijing University of Chinese Medicine, Beijing, China
| | - Xudan Wang
- Department of Microbiology and Immunology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Söderholm S, Fu Y, Gaelings L, Belanov S, Yetukuri L, Berlinkov M, Cheltsov AV, Anders S, Aittokallio T, Nyman TA, Matikainen S, Kainov DE. Multi-Omics Studies towards Novel Modulators of Influenza A Virus-Host Interaction. Viruses 2016; 8:v8100269. [PMID: 27690086 PMCID: PMC5086605 DOI: 10.3390/v8100269] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 09/13/2016] [Accepted: 09/22/2016] [Indexed: 12/20/2022] Open
Abstract
Human influenza A viruses (IAVs) cause global pandemics and epidemics. These viruses evolve rapidly, making current treatment options ineffective. To identify novel modulators of IAV–host interactions, we re-analyzed our recent transcriptomics, metabolomics, proteomics, phosphoproteomics, and genomics/virtual ligand screening data. We identified 713 potential modulators targeting 199 cellular and two viral proteins. Anti-influenza activity for 48 of them has been reported previously, whereas the antiviral efficacy of the 665 remains unknown. Studying anti-influenza efficacy and immuno/neuro-modulating properties of these compounds and their combinations as well as potential viral and host resistance to them may lead to the discovery of novel modulators of IAV–host interactions, which might be more effective than the currently available anti-influenza therapeutics.
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Affiliation(s)
- Sandra Söderholm
- Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
- Finnish Institute of Occupational Health, Helsinki 00250, Finland.
| | - Yu Fu
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
| | - Lana Gaelings
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
| | - Sergey Belanov
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
| | - Laxman Yetukuri
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
| | - Mikhail Berlinkov
- Institute of Mathematics and Computer Science, Ural Federal University, Yekaterinburg 620083, Russia.
| | - Anton V Cheltsov
- Q-Mol L.L.C. in Silico Pharmaceuticals, San Diego, CA 92037, USA.
| | - Simon Anders
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
| | - Tero Aittokallio
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
- Department of Mathematics and Statistics, University of Turku, Turku 20014, Finland.
| | | | - Sampsa Matikainen
- Finnish Institute of Occupational Health, Helsinki 00250, Finland.
- Department of Rheumatology, Helsinki University Hospital, University of Helsinki, Helsinki 00015, Finland.
| | - Denis E Kainov
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
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Marois I, Cloutier A, Meunier I, Weingartl HM, Cantin AM, Richter MV. Inhibition of influenza virus replication by targeting broad host cell pathways. PLoS One 2014; 9:e110631. [PMID: 25333287 PMCID: PMC4204995 DOI: 10.1371/journal.pone.0110631] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 09/24/2014] [Indexed: 12/19/2022] Open
Abstract
Antivirals that are currently used to treat influenza virus infections target components of the virus which can mutate rapidly. Consequently, there has been an increase in the number of resistant strains to one or many antivirals in recent years. Here we compared the antiviral effects of lysosomotropic alkalinizing agents (LAAs) and calcium modulators (CMs), which interfere with crucial events in the influenza virus replication cycle, against avian, swine, and human viruses of different subtypes in MDCK cells. We observed that treatment with LAAs, CMs, or a combination of both, significantly inhibited viral replication. Moreover, the drugs were effective even when they were administered 8 h after infection. Finally, analysis of the expression of viral acidic polymerase (PA) revealed that both drugs classes interfered with early events in the viral replication cycle. This study demonstrates that targeting broad host cellular pathways can be an efficient strategy to inhibit influenza replication. Furthermore, it provides an interesting avenue for drug development where resistance by the virus might be reduced since the virus is not targeted directly.
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Affiliation(s)
- Isabelle Marois
- Department of Medicine, Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Centre de Recherche du CHUS, Sherbrooke, Québec, Canada
| | - Alexandre Cloutier
- Department of Medicine, Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Centre de Recherche du CHUS, Sherbrooke, Québec, Canada
| | - Isabelle Meunier
- Department of Medicine, Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Centre de Recherche du CHUS, Sherbrooke, Québec, Canada
| | - Hana M. Weingartl
- National Centre for Foreign Animal Disease, Canadian Food Inspection Agency, Winnipeg, Manitoba, Canada, and Department of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - André M. Cantin
- Department of Medicine, Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Centre de Recherche du CHUS, Sherbrooke, Québec, Canada
| | - Martin V. Richter
- Department of Medicine, Pulmonary Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada
- Centre de Recherche du CHUS, Sherbrooke, Québec, Canada
- * E-mail:
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Haidari M, Zhang W, Ganjehei L, Ali M, Chen Z. Inhibition of MLC phosphorylation restricts replication of influenza virus--a mechanism of action for anti-influenza agents. PLoS One 2011; 6:e21444. [PMID: 21731751 PMCID: PMC3121769 DOI: 10.1371/journal.pone.0021444] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 05/28/2011] [Indexed: 01/21/2023] Open
Abstract
Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds.
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Affiliation(s)
- Mehran Haidari
- Department of Internal Medicine, Division of Cardiology, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
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Sasvari Z, Bach S, Blondel M, Nagy PD. Inhibition of RNA recruitment and replication of an RNA virus by acridine derivatives with known anti-prion activities. PLoS One 2009; 4:e7376. [PMID: 19823675 PMCID: PMC2757906 DOI: 10.1371/journal.pone.0007376] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2009] [Accepted: 08/27/2009] [Indexed: 11/24/2022] Open
Abstract
Background Small molecule inhibitors of RNA virus replication are potent antiviral drugs and useful to dissect selected steps in the replication process. To identify antiviral compounds against Tomato bushy stunt virus (TBSV), a model positive stranded RNA virus, we tested acridine derivatives, such as chlorpromazine (CPZ) and quinacrine (QC), which are active against prion-based diseases. Methodology/Principal Findings Here, we report that CPZ and QC compounds inhibited TBSV RNA accumulation in plants and in protoplasts. In vitro assays revealed that the inhibitory effects of these compounds were manifested at different steps of TBSV replication. QC was shown to have an effect on multiple steps, including: (i) inhibition of the selective binding of the p33 replication protein to the viral RNA template, which is required for recruitment of viral RNA for replication; (ii) reduction of minus-strand synthesis by the tombusvirus replicase; and (iii) inhibition of translation of the uncapped TBSV genomic RNA. In contrast, CPZ was shown to inhibit the in vitro assembly of the TBSV replicase, likely due to binding of CPZ to intracellular membranes, which are important for RNA virus replication. Conclusion/Significance Since we found that CPZ was also an effective inhibitor of other plant viruses, including Tobacco mosaic virus and Turnip crinkle virus, it seems likely that CPZ has a broad range of antiviral activity. Thus, these inhibitors constitute effective tools to study similarities in replication strategies of various RNA viruses.
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Affiliation(s)
- Zsuzsanna Sasvari
- Department of Plant Pathology, University of Kentucky, Lexington, Kentucky, United States of America
| | - Stéphane Bach
- USR3151-CNRS “Protein Phosphorylation & Human Disease”, Station Biologique, B.P. 74, 29682 Roscoff cedex, Bretagne, France
| | - Marc Blondel
- INSERM U613, Brest, France
- Univ Brest, Faculté de Médecine et des Sciences de la Santé, UMR-S613, Brest, France
- Etablissement Français du Sang (EFS) Bretagne, Brest, France
- CHU Brest, Hop Morvan, Laboratoire de Génétique Moléculaire, Brest, France
| | - Peter D. Nagy
- Department of Plant Pathology, University of Kentucky, Lexington, Kentucky, United States of America
- * E-mail:
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Marjuki H, Alam MI, Ehrhardt C, Wagner R, Planz O, Klenk HD, Ludwig S, Pleschka S. Membrane accumulation of influenza A virus hemagglutinin triggers nuclear export of the viral genome via protein kinase Calpha-mediated activation of ERK signaling. J Biol Chem 2006; 281:16707-15. [PMID: 16608852 DOI: 10.1074/jbc.m510233200] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Replication and transcription of the influenza virus genome takes place exclusively within the nucleus of the infected cells. The viral RNA genome, polymerase subunits, and nucleoprotein form ribonucleoprotein (RNP) complexes. Late in the infectious cycle RNPs have to be exported from the nucleus to be enwrapped into budding progeny virions at the cell membrane. This process requires viral activation of the cellular Raf/MEK/ERK (mitogen-activated protein kinase (MAPK)) signaling cascade that is activated late in the infection cycle. Accordingly, block of the cascade results in retardation of RNP export and reduced titers of progeny virus. In the present study we have analyzed the importance of cell-membrane association of the viral hemagglutinin glycoprotein for viral MAPK activation. We show that hemagglutinin membrane accumulation and its tight association with lipid-raft domains trigger activation of the MAPK cascade via protein kinase Calpha activation and induces RNP export. This may represent an auto-regulative mechanism that coordinates timing of RNP export to a point when all viral components are ready for virus budding.
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Affiliation(s)
- Henju Marjuki
- Institute for Medical Virology, Justus-Liebig-University, Frankfurter Strasse 107, D-35392 Giessen, Germany
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Lefkowitz SS, Vaz A, Lincoln J, Cain T, Brown DJ, Lefkowitz DL. Alteration of macrophage functions by cocaine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1996; 402:135-44. [PMID: 8787654 DOI: 10.1007/978-1-4613-0407-4_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- S S Lefkowitz
- Department of Microbiology and Immunology, Texas Tech University Health Sciences Center, Lubbock 79430, USA
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Schlesinger MJ, Cahill D. Verapamil and chlorpromazine inhibit the budding of Sindbis and vesicular stomatitis viruses from infected chicken embryo fibroblasts. Virology 1989; 168:187-90. [PMID: 2535903 DOI: 10.1016/0042-6822(89)90421-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Two agents, verapamil and chlorpromazine, which affect calcium levels in cells were tested as inhibitors of Sindbis and vesicular stomatitis virus replication in chicken embryo fibroblasts. At levels which did not greatly inhibit general protein synthesis, both drugs appeared to selectively block virus formation at the final stages of virus assembly and budding. Viral nucleoprotein synthesis and transport of viral glycoproteins to the cell plasma membrane were not inhibited under conditions that blocked virus particle release into the cell culture medium. The effects of the drugs were reversible but no morphologically distinct virus-specific structures were detected in the inhibited cells.
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Affiliation(s)
- M J Schlesinger
- Department of Microbiology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110
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Lewis MG, Chang JY, Olsen RG, Fertel RH. Identification of calmodulin activity in purified retroviruses. Biochem Biophys Res Commun 1986; 141:1077-83. [PMID: 3028385 DOI: 10.1016/s0006-291x(86)80153-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Several viruses have been shown to require calcium for their function, and to bind calcium at specific sites. However, the nature of the calcium binding molecule on viruses has not been established. One possibility is the ubiquitous calcium-binding protein calmodulin. Our studies were designed to determine whether feline leukemia virus contained calmodulin. Accordingly, we tested purified feline leukemia virus for the presence of calmodulin-like activity. The virus, like authentic calmodulin, activated cyclic AMP phosphodiesterase. The ability of the virus to activate the enzyme was blocked in the presence of the known calmodulin inhibitors trifluoperazine and W-7. This indirect evidence for the presence of calmodulin was confirmed by radioimmunoassay. Several other retroviruses were also tested using radioimmunoassay and found to contain calmodulin. Our results indicate that the calcium binding site in retroviruses may be calmodulin.
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