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1
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Thierry AR, Salmon D. Inflammation-, immunothrombosis,- and autoimmune-feedback loops may lead to persistent neutrophil self-stimulation in long COVID. J Med Virol 2024; 96:e29887. [PMID: 39189651 DOI: 10.1002/jmv.29887] [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: 03/28/2024] [Revised: 07/10/2024] [Accepted: 08/13/2024] [Indexed: 08/28/2024]
Abstract
Understanding the pathophysiology of long COVID is one of the most intriguing challenges confronting contemporary medicine. Despite observations recently made in the relevant molecular, cellular, and physiological domains, it is still difficult to say whether the post-acute sequelae of COVID-19 directly correspond to the consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This work hypothesizes that neutrophils and neutrophil extracellular traps (NETs) production are at the interconnection of three positive feedback loops which are initiated in the acute phase of SARS-CoV-2 infection, and which involve inflammation, immunothrombosis, and autoimmunity. This phenomenon could be favored by the fact that SARS-CoV-2 may directly bind and penetrate neutrophils. The ensuing strong neutrophil stimulation leads to a progressive amplification of an exacerbated and uncontrolled NETs production, potentially persisting for months beyond the acute phase of infection. This continuous self-stimulation of neutrophils leads, in turn, to systemic inflammation, micro-thromboses, and the production of autoantibodies, whose significant consequences include the persistence of endothelial and multiorgan damage, and vascular complications.
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Affiliation(s)
- Alain R Thierry
- IRCM, Institute of Research on Cancerology of Montpellier, INSERM U1194, University of Montpellier, Montpellier, France
- Montpellier Cancer Institute (ICM), Montpellier, France
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2
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Padín JF, Pérez-Ortiz JM, Redondo-Calvo FJ. Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function. Int J Mol Sci 2024; 25:7553. [PMID: 39062796 PMCID: PMC11277036 DOI: 10.3390/ijms25147553] [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: 05/27/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024] Open
Abstract
Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin-kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin-angiotensin-aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled "Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions", we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.
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Affiliation(s)
- Juan Fernando Padín
- Department of Medical Sciences, School of Medicine at Ciudad Real, University of Castilla-La Mancha, 13971 Ciudad Real, Spain;
| | - José Manuel Pérez-Ortiz
- Facultad HM de Ciencias de la Salud, Universidad Camilo José Cela, 28692 Madrid, Spain
- Instituto de Investigación Sanitaria HM Hospitales, 28015 Madrid, Spain
| | - Francisco Javier Redondo-Calvo
- Department of Medical Sciences, School of Medicine at Ciudad Real, University of Castilla-La Mancha, 13971 Ciudad Real, Spain;
- Department of Anaesthesiology and Critical Care Medicine, University General Hospital, 13005 Ciudad Real, Spain
- Translational Research Unit, University General Hospital and Research Institute of Castilla-La Mancha (IDISCAM), 13005 Ciudad Real, Spain
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3
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Lubinski B, Whittaker GR. Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review. Viruses 2024; 16:984. [PMID: 38932275 PMCID: PMC11209347 DOI: 10.3390/v16060984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.
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Affiliation(s)
- Bailey Lubinski
- Department of Microbiology & Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA;
| | - Gary R. Whittaker
- Department of Microbiology & Immunology and Public & Ecosystem Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA
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4
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An D, Li Z, Beavis AC, Briggs KR, Harvill M, He B. Cleavage of the syncytial protein of J paramyxovirus is required for its ability to promote cell-cell fusion. Proc Natl Acad Sci U S A 2024; 121:e2403389121. [PMID: 38833471 PMCID: PMC11181024 DOI: 10.1073/pnas.2403389121] [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: 02/17/2024] [Accepted: 05/02/2024] [Indexed: 06/06/2024] Open
Abstract
Cell-cell fusion mediated by most paramyxovirus requires fusion protein (F) and attachment protein (H, HN, or G). The F protein is proteolytic cleaved to be fusogenically active. J paramyxovirus (JPV) has a unique feature in the family Paramyxoviridae: It encodes an integral membrane protein, syncytial protein (SP, formerly known as transmembrane protein, TM), which is essential in JPV-promoted cell-cell fusion (i.e., syncytial). In this study, we report that cleavage of SP is essential for its syncytial-promoting activity. We have identified the cleavage site of SP at amino acid residues 172 to 175, LKTG, and deletion of the "LKTG" residues abolished SP protein cleavage and its ability to promote cell-cell fusion. Replacing the cleavage site LKTG with a factor Xa protease cleavage site allows cleavage of the SP with factor Xa protease and restores its ability to promote cell-cell fusion. Furthermore, results from a hemifusion assay indicate that cleavage of SP plays an important role in the progression from the intermediate hemifusion state to a complete fusion. This work indicates that SP has many characteristics of a fusion protein. We propose that SP is likely a cell-cell fusion-promoting protein.
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Affiliation(s)
- Dong An
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA30602
| | - Zhuo Li
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA30602
| | - Ashley C. Beavis
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA30602
| | - Kelsey R. Briggs
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA30602
| | - Mason Harvill
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA30602
| | - Biao He
- Department of Infectious Diseases, University of Georgia College of Veterinary Medicine, Athens, GA30602
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5
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Visser N, Herreman LCM, Vandooren J, Pereira RVS, Opdenakker G, Spelbrink REJ, Wilbrink MH, Bremer E, Gosens R, Nawijn MC, van der Ende-Metselaar HH, Smit JM, Laus MC, Laman JD. Novel high-yield potato protease inhibitor panels block a wide array of proteases involved in viral infection and crucial tissue damage. J Mol Med (Berl) 2024; 102:521-536. [PMID: 38381158 PMCID: PMC10963447 DOI: 10.1007/s00109-024-02423-x] [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: 01/17/2024] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 02/22/2024]
Abstract
Viruses critically rely on various proteases to ensure host cell entry and replication. In response to viral infection, the host will induce acute tissue inflammation pulled by granulocytes. Upon hyperactivation, neutrophil granulocytes may cause undue tissue damage through proteolytic degradation of the extracellular matrix. Here, we assess the potential of protease inhibitors (PI) derived from potatoes in inhibiting viral infection and reducing tissue damage. The original full spectrum of potato PI was developed into five fractions by means of chromatography and hydrolysis. Individual fractions showed varying inhibitory efficacy towards a panel of proteases including trypsin, chymotrypsin, ACE2, elastase, and cathepsins B and L. The fractions did not interfere with SARS-CoV-2 infection of Vero E6 cells in vitro. Importantly, two of the fractions fully inhibited elastin-degrading activity of complete primary human neutrophil degranulate. These data warrant further development of potato PI fractions for biomedical purposes, including tissue damage crucial to SARS-CoV-2 pathogenesis. KEY MESSAGES: Protease inhibitor fractions from potato differentially inhibit a series of human proteases involved in viral replication and in tissue damage by overshoot inflammation. Protease inhibition of cell surface receptors such as ACE2 does not prevent virus infection of Vero cells in vitro. Protease inhibitors derived from potato can fully inhibit elastin-degrading primary human neutrophil proteases. Protease inhibitor fractions can be produced at high scale (hundreds of thousands of kilograms, i.e., tons) allowing economically feasible application in lower and higher income countries.
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Affiliation(s)
- Nienke Visser
- Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands
| | | | - Jennifer Vandooren
- Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000, Louvain, Belgium
| | - Rafaela Vaz Sousa Pereira
- Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000, Louvain, Belgium
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology, Immunology and Transplantation, KU Leuven, 3000, Louvain, Belgium
| | | | | | - Edwin Bremer
- Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands
| | - Reinoud Gosens
- Department of Molecular Pharmacology, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands
- Groningen Research Institute for Asthma and COPD (GRIAC) Research Institute, University of Groningen, 9713 GZ, Groningen, The Netherlands
| | - Martijn C Nawijn
- Groningen Research Institute for Asthma and COPD (GRIAC) Research Institute, University of Groningen, 9713 GZ, Groningen, The Netherlands
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands
| | - Heidi H van der Ende-Metselaar
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands
| | - Jolanda M Smit
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands
| | - Marc C Laus
- Avebe Innovation Center Groningen, 9747 AW, Groningen, The Netherlands
| | - Jon D Laman
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ, Groningen, The Netherlands.
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6
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Hamdy ME, El Deeb AH, Hagag NM, Shahein MA, Alaidi O, Hussein HA. Interspecies transmission of SARS CoV-2 with special emphasis on viral mutations and ACE-2 receptor homology roles. Int J Vet Sci Med 2023; 11:55-86. [PMID: 37441062 PMCID: PMC10334861 DOI: 10.1080/23144599.2023.2222981] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 05/11/2023] [Accepted: 05/19/2023] [Indexed: 07/15/2023] Open
Abstract
COVID-19 outbreak was first reported in 2019, Wuhan, China. The spillover of the disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), to a wide range of pet, zoo, wild, and farm animals has emphasized potential zoonotic and reverse zoonotic viral transmission. Furthermore, it has evoked inquiries about susceptibility of different animal species to SARS-CoV-2 infection and role of these animals as viral reservoirs. Therefore, studying susceptible and non-susceptible hosts for SARS-CoV-2 infection could give a better understanding for the virus and will help in preventing further outbreaks. Here, we review structural aspects of SARS-CoV-2 spike protein, the effect of the different mutations observed in the spike protein, and the impact of ACE2 receptor variations in different animal hosts on inter-species transmission. Moreover, the SARS-CoV-2 spillover chain was reviewed. Combination of SARS-CoV-2 high mutation rate and homology of cellular ACE2 receptors enable the virus to transcend species barriers and facilitate its transmission between humans and animals.
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Affiliation(s)
- Mervat E. Hamdy
- Genome Research Unit, Animal Health Research Institute, Agriculture Research Centre, Giza, Egypt
| | - Ayman H. El Deeb
- Department of Virology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
- Department of Virology, Faculty of Veterinary Medicine, King Salman International University, South Sinai, Egypt
| | - Naglaa M. Hagag
- Genome Research Unit, Animal Health Research Institute, Agriculture Research Centre, Giza, Egypt
| | - Momtaz A. Shahein
- Department of Virology, Animal Health Research Institute, Agriculture Research Centre, Giza, Egypt
| | - Osama Alaidi
- Biocomplexity for Research and Consulting Co., Cairo, Egypt
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Hussein A. Hussein
- Department of Virology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
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7
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Halsey G, Sinha D, Dhital S, Wang X, Vyavahare N. Role of elastic fiber degradation in disease pathogenesis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166706. [PMID: 37001705 PMCID: PMC11659964 DOI: 10.1016/j.bbadis.2023.166706] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023]
Abstract
Elastin is a crucial extracellular matrix protein that provides structural integrity to tissues. Crosslinked elastin and associated microfibrils, named elastic fiber, contribute to biomechanics by providing the elasticity required for proper function. During aging and disease, elastic fiber can be progressively degraded and since there is little elastin synthesis in adults, degraded elastic fiber is not regenerated. There is substantial evidence linking loss or damage of elastic fibers to the clinical manifestation and pathogenesis of a variety of diseases. Disruption of elastic fiber networks by hereditary mutations, aging, or pathogenic stimuli results in systemic ailments associated with the production of elastin degradation products, inflammatory responses, and abnormal physiology. Due to its longevity, unique mechanical properties, and widespread distribution in the body, elastic fiber plays a central role in homeostasis of various physiological systems. While pathogenesis related to elastic fiber degradation has been more thoroughly studied in elastic fiber rich tissues such as the vasculature and the lungs, even tissues containing relatively small quantities of elastic fibers such as the eyes or joints may be severely impacted by elastin degradation. Elastic fiber degradation is a common observation in certain hereditary, age, and specific risk factor exposure induced diseases representing a converging point of pathological clinical phenotypes which may also help explain the appearance of co-morbidities. In this review, we will first cover the role of elastic fiber degradation in the manifestation of hereditary diseases then individually explore the structural role and degradation effects of elastic fibers in various tissues and organ systems. Overall, stabilizing elastic fiber structures and repairing lost elastin may be effective strategies to reverse the effects of these diseases.
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Affiliation(s)
- Gregory Halsey
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Dipasha Sinha
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Saphala Dhital
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Xiaoying Wang
- Department of Bioengineering, Clemson University, SC 29634, United States of America
| | - Naren Vyavahare
- Department of Bioengineering, Clemson University, SC 29634, United States of America.
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8
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Stevens CS, Oguntuyo KY, Kowdle S, Brambilla L, Haas G, Gowlikar A, Siddiquey MN, Schilke RM, Woolard MD, Zhang H, Acklin JA, Ikegame S, Huang CT, Lim JK, Cross RW, Geisbert TW, Ivanov SS, Kamil JP, Lee B. Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2020.08.14.248880. [PMID: 32817940 PMCID: PMC7430570 DOI: 10.1101/2020.08.14.248880] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Rationale SARS-CoV-2 entry into host cells is facilitated by endogenous and exogenous proteases that proteolytically activate the spike glycoprotein and antiproteases inhibiting this process. Understanding the key actors in viral entry is crucial for advancing knowledge of virus tropism, pathogenesis, and potential therapeutic targets. Objectives We aimed to investigate the role of naïve serum and alpha-1-antitrypsin (AAT) in inhibiting protease-mediated SARS-CoV-2 entry and explore the implications of AAT deficiency on susceptibility to different SARS-CoV-2 variants. Findings Our study demonstrates that naïve serum exhibits significant inhibition of SARS-CoV-2 entry, with AAT identified as the major serum protease inhibitor potently restricting entry. Using pseudoparticles, replication-competent pseudoviruses, and authentic SARS-CoV-2, we show that AAT inhibition occurs at low concentrations compared with those in serum and bronchoalveolar tissues, suggesting physiological relevance. Furthermore, sera from subjects with an AAT-deficient genotype show reduced ability to inhibit entry of both Wuhan-Hu-1 (WT) and B.1.617.2 (Delta) but exhibit no difference in inhibiting B.1.1.529 (Omicron) entry. Conclusions AAT may have a variant-dependent therapeutic potential against SARS-CoV-2. Our findings highlight the importance of further investigating the complex interplay between proteases, antiproteases, and spike glycoprotein activation in SARS-CoV-2 and other respiratory viruses to identify potential therapeutic targets and improve understanding of disease pathogenesis.
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Affiliation(s)
- Christian S Stevens
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | | | - Shreyas Kowdle
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Luca Brambilla
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Griffin Haas
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Aditya Gowlikar
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Mohammed Na Siddiquey
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103
| | - Robert M Schilke
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103
| | - Matthew D Woolard
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103
| | - Hongbo Zhang
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103
| | - Joshua A Acklin
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Satoshi Ikegame
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Chuan-Tien Huang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Jean K Lim
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Robert W Cross
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555
| | - Thomas W Geisbert
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555
| | - Stanimir S Ivanov
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103
| | - Jeremy P Kamil
- Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103
| | - Benhur Lee
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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9
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Zabiegala A, Kim Y, Chang KO. Roles of host proteases in the entry of SARS-CoV-2. ANIMAL DISEASES 2023; 3:12. [PMID: 37128508 PMCID: PMC10125864 DOI: 10.1186/s44149-023-00075-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 03/07/2023] [Indexed: 05/03/2023] Open
Abstract
The spike protein (S) of SARS-CoV-2 is responsible for viral attachment and entry, thus a major factor for host susceptibility, tissue tropism, virulence and pathogenicity. The S is divided with S1 and S2 region, and the S1 contains the receptor-binding domain (RBD), while the S2 contains the hydrophobic fusion domain for the entry into the host cell. Numerous host proteases have been implicated in the activation of SARS-CoV-2 S through various cleavage sites. In this article, we review host proteases including furin, trypsin, transmembrane protease serine 2 (TMPRSS2) and cathepsins in the activation of SARS-CoV-2 S. Many betacoronaviruses including SARS-CoV-2 have polybasic residues at the S1/S2 site which is subjected to the cleavage by furin. The S1/S2 cleavage facilitates more assessable RBD to the receptor ACE2, and the binding triggers further conformational changes and exposure of the S2' site to proteases such as type II transmembrane serine proteases (TTPRs) including TMPRSS2. In the presence of TMPRSS2 on the target cells, SARS-CoV-2 can utilize a direct entry route by fusion of the viral envelope to the cellular membrane. In the absence of TMPRSS2, SARS-CoV-2 enter target cells via endosomes where multiple cathepsins cleave the S for the successful entry. Additional host proteases involved in the cleavage of the S were discussed. This article also includes roles of 3C-like protease inhibitors which have inhibitory activity against cathepsin L in the entry of SARS-CoV-2, and discussed the dual roles of such inhibitors in virus replication.
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Affiliation(s)
- Alexandria Zabiegala
- Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, Manhattan, KS 66506 USA
| | - Yunjeong Kim
- Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, Manhattan, KS 66506 USA
| | - Kyeong-Ok Chang
- Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, 1800 Denison Avenue, Manhattan, KS 66506 USA
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10
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Sardar A, Bera T, Kumar Samal S, Dewangan N, Kamble M, Guha S, Tarafdar PK. C-Terminal Lipidation of SARS-CoV-2 Fusion Peptide Reinstates Superior Membrane Fusion Catalytic Ability. Chemistry 2023; 29:e202203034. [PMID: 36422064 DOI: 10.1002/chem.202203034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/16/2022] [Accepted: 11/17/2022] [Indexed: 11/25/2022]
Abstract
The spike (S) protein of severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) mediates a critical stage in infection, the fusion between viral and host membranes. The protein is categorized as a class I viral fusion protein and has two distinct cleavage sites that can be activated by proteases. The activation deploys the fusion peptide (FP) for insertion into the target cell membranes. Recent studies including our experiments showed that the FP was unable to modulate the kinetics of fusion at a low peptide-to-lipid ratio akin to the spike density at the viral surface. Therefore, we modified the C terminus of FP and attached a myristoyl chain (C-myr-FP) to restrict the C terminus near to the interface, bridge both membranes, and increase the effective local concentration. The lipidated FP (C-myr-FP) of SARS-CoV-2 greatly accelerates membrane fusion at a low peptide-to-lipid ratio as compared to the FP with no lipidation. Biophysical experiments suggest that C-myr-FP adopts a helical structure, perturbs the membrane interface, and increases water penetration to catalyze fusion. Scrambled peptide (C-myr-sFP) and truncated peptide (C-myr-8FP) could not significantly catalyze the fusion, thus suggesting the important role of myristoylation and the N terminus. C-myr-FP enhances murine coronavirus infection by promoting syncytia formation in L2 cells. The C-terminal lipidation of the FP might be a useful strategy to induce artificial fusion in biomedical applications.
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Affiliation(s)
- Avijit Sardar
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
| | - Tapas Bera
- Department of Chemistry, Jadavpur University, 700032, Kolkata, India
| | - Santosh Kumar Samal
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
| | - Nikesh Dewangan
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
| | - Mithila Kamble
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
| | - Samit Guha
- Department of Chemistry, Jadavpur University, 700032, Kolkata, India
| | - Pradip K Tarafdar
- Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, 741246, Mohanpur, India
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11
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Permethrin as a Potential Furin Inhibitor through a Novel Non-Competitive Allosteric Inhibition. Molecules 2023; 28:molecules28041883. [PMID: 36838867 PMCID: PMC9959265 DOI: 10.3390/molecules28041883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Furin is a potential target protein associated with numerous diseases; especially closely related to tumors and multiple viral infections including SARS-CoV-2. Most of the existing efficient furin inhibitors adopt a substrate analogous structure, and other types of small molecule inhibitors need to be discovered urgently. In this study, a high-throughput screening combining virtual and physical screening of natural product libraries was performed, coupled with experimental validation and preliminary mechanistic assays at the molecular level, cellular level, and molecular simulation. A novel furin inhibitor, permethrin, which is a derivative from pyrethrin I generated by Pyrethrum cinerariifolium Trev. was identified, and this study confirmed that it binds to a novel allosteric pocket of furin through non-competitive inhibition. It exhibits a very favorable protease-selective inhibition and good cellular activity and specificity. In summary, permethrin shows a new parent nucleus with a new mode of inhibition. It could be used as a highly promising lead compound against furin for targeting related tumors and various resistant viral infections, including SARS-CoV-2.
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12
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Nejat R, Torshizi MF, Najafi DJ. S Protein, ACE2 and Host Cell Proteases in SARS-CoV-2 Cell Entry and Infectivity; Is Soluble ACE2 a Two Blade Sword? A Narrative Review. Vaccines (Basel) 2023; 11:204. [PMID: 36851081 PMCID: PMC9968219 DOI: 10.3390/vaccines11020204] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/07/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
Since the spread of the deadly virus SARS-CoV-2 in late 2019, researchers have restlessly sought to unravel how the virus enters the host cells. Some proteins on each side of the interaction between the virus and the host cells are involved as the major contributors to this process: (1) the nano-machine spike protein on behalf of the virus, (2) angiotensin converting enzyme II, the mono-carboxypeptidase and the key component of renin angiotensin system on behalf of the host cell, (3) some host proteases and proteins exploited by SARS-CoV-2. In this review, the complex process of SARS-CoV-2 entrance into the host cells with the contribution of the involved host proteins as well as the sequential conformational changes in the spike protein tending to increase the probability of complexification of the latter with angiotensin converting enzyme II, the receptor of the virus on the host cells, are discussed. Moreover, the release of the catalytic ectodomain of angiotensin converting enzyme II as its soluble form in the extracellular space and its positive or negative impact on the infectivity of the virus are considered.
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Affiliation(s)
- Reza Nejat
- Department of Anesthesiology and Critical Care Medicine, Laleh Hospital, Tehran 1467684595, Iran
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13
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ZENG W, SONG Y, WANG R, HE R, WANG T. Neutrophil elastase: From mechanisms to therapeutic potential. J Pharm Anal 2023; 13:355-366. [PMID: 37181292 PMCID: PMC10173178 DOI: 10.1016/j.jpha.2022.12.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/30/2022] [Accepted: 12/31/2022] [Indexed: 01/09/2023] Open
Abstract
Neutrophil elastase (NE), a major protease in the primary granules of neutrophils, is involved in microbicidal activity. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process. NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling. However, NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction. Additionally, it plays a complex role in various physiological processes and mediates several diseases. Sivelestat, a specific NE inhibitor, has strong potential for clinical application, particularly in the treatment of coronavirus disease 2019 (COVID-19). This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.
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14
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COVID-19 Pathology Sheds Further Light on Balance between Neutrophil Proteases and Their Inhibitors. Biomolecules 2022; 13:biom13010082. [PMID: 36671467 PMCID: PMC9855895 DOI: 10.3390/biom13010082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/26/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the concomitant release of granule contents that damage surrounding tissues into sharp focus. Neutrophil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. Interestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promotes lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) and increases the risk of allergic responses. Recent observations point to the fact that reduced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19.
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15
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Jahanimoghadam A, Abdolahzadeh H, Rad NK, Zahiri J. Discovering Common Pathogenic Mechanisms of COVID-19 and Parkinson Disease: An Integrated Bioinformatics Analysis. J Mol Neurosci 2022; 72:2326-2337. [PMID: 36301487 PMCID: PMC9607846 DOI: 10.1007/s12031-022-02068-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 09/13/2022] [Indexed: 12/14/2022]
Abstract
Coronavirus disease 2019 (COVID-19) has emerged since December 2019 and was later characterized as a pandemic by WHO, imposing a major public health threat globally. Our study aimed to identify common signatures from different biological levels to enlighten the current unclear association between COVID-19 and Parkinson's disease (PD) as a number of possible links, and hypotheses were reported in the literature. We have analyzed transcriptome data from peripheral blood mononuclear cells (PBMCs) of both COVID-19 and PD patients, resulting in a total of 81 common differentially expressed genes (DEGs). The functional enrichment analysis of common DEGs are mostly involved in the complement system, type II interferon gamma (IFNG) signaling pathway, oxidative damage, microglia pathogen phagocytosis pathway, and GABAergic synapse. The protein-protein interaction network (PPIN) construction was carried out followed by hub detection, revealing 10 hub genes (MX1, IFI27, C1QC, C1QA, IFI6, NFIX, C1S, XAF1, IFI35, and ELANE). Some of the hub genes were associated with molecular mechanisms such as Lewy bodies-induced inflammation, microglia activation, and cytokine storm. We investigated regulatory elements of hub genes at transcription factor and miRNA levels. The major transcription factors regulating hub genes are SOX2, XAF1, RUNX1, MITF, and SPI1. We propose that these events may have important roles in the onset or progression of PD. To sum up, our analysis describes possible mechanisms linking COVID-19 and PD, elucidating some unknown clues in between.
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Affiliation(s)
- Aria Jahanimoghadam
- Bioinformatics and Computational Omics Lab (BioCOOL), Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
- Biocenter, Julius-Maximilians-Universität Würzburg, Am Hubland, Würzburg, Germany
| | - Hadis Abdolahzadeh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Javad Zahiri
- Department of Neuroscience, University of California San Diego, La Jolla, San Diego, CA, USA.
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16
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Jasim SA, Mahdi RS, Bokov DO, Najm MAA, Sobirova GN, Bafoyeva ZO, Taifi A, Alkadir OKA, Mustafa YF, Mirzaei R, Karampoor S. The deciphering of the immune cells and marker signature in COVID-19 pathogenesis: An update. J Med Virol 2022; 94:5128-5148. [PMID: 35835586 PMCID: PMC9350195 DOI: 10.1002/jmv.28000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/28/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022]
Abstract
The precise interaction between the immune system and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical in deciphering the pathogenesis of coronavirus disease 2019 (COVID-19) and is also vital for developing novel therapeutic tools, including monoclonal antibodies, antivirals drugs, and vaccines. Viral infections need innate and adaptive immune reactions since the various immune components, such as neutrophils, macrophages, CD4+ T, CD8+ T, and B lymphocytes, play different roles in various infections. Consequently, the characterization of innate and adaptive immune reactions toward SARS-CoV-2 is crucial for defining the pathogenicity of COVID-19. In this study, we explain what is currently understood concerning the conventional immune reactions to SARS-CoV-2 infection to shed light on the protective and pathogenic role of immune response in this case. Also, in particular, we investigate the in-depth roles of other immune mediators, including neutrophil elastase, serum amyloid A, and syndecan, in the immunopathogenesis of COVID-19.
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Affiliation(s)
| | - Roaa Salih Mahdi
- Department of Pathology, College of MedicineUniversity of BabylonHillaIraq
| | - Dmitry Olegovich Bokov
- Institute of PharmacySechenov First Moscow State Medical UniversityMoscowRussian Federation
- Laboratory of Food ChemistryFederal Research Center of Nutrition, Biotechnology and Food SafetyMoscowRussian Federation
| | - Mazin A. A. Najm
- Pharmaceutical Chemistry Department, College of PharmacyAl‐Ayen UniversityThi‐QarIraq
| | - Guzal N. Sobirova
- Department of Rehabilitation, Folk Medicine and Physical EducationTashkent Medical AcademyTashkentUzbekistan
| | - Zarnigor O. Bafoyeva
- Department of Rehabilitation, Folk Medicine and Physical EducationTashkent Medical AcademyTashkentUzbekistan
| | | | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of PharmacyUniversity of MosulMosulIraq
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research CenterPasteur Institute of IranTehranIran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research CenterIran University of Medical SciencesTehranIran
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17
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Kastenhuber ER, Mercadante M, Nilsson-Payant B, Johnson JL, Jaimes JA, Muecksch F, Weisblum Y, Bram Y, Whittaker GR, tenOever BR, Schwartz RE, Chandar V, Cantley L. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry. eLife 2022; 11:77444. [PMID: 35294338 PMCID: PMC8942469 DOI: 10.7554/elife.77444] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 02/22/2022] [Indexed: 11/13/2022] Open
Abstract
Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases and coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.
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Affiliation(s)
| | - Marisa Mercadante
- Department of Medicine, Weill Cornell Medical College, New York, United States
| | - Benjamin Nilsson-Payant
- Institute of Experimental Virology, TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH, Hannover, Germany
| | - Jared L Johnson
- Department of Medicine, Weill Cornell Medical College, New York, United States
| | - Javier A Jaimes
- Department of Microbiology and Immunology, Cornell University, Ithaca, United States
| | - Frauke Muecksch
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
| | - Yiska Weisblum
- Laboratory of Retrovirology, The Rockefeller University, New York, United States
| | - Yaron Bram
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Gary R Whittaker
- Department of Microbiology and Immunology, Cornell University, Ithaca, United States
| | - Benjamin R tenOever
- Department of Microbiology, New York University Langone Medical Center, New York, United States
| | - Robert E Schwartz
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Vasuretha Chandar
- Department of Medicine, Weill Cornell Medicine, New York, United States
| | - Lewis Cantley
- Department of Medicine, Weill Cornell Medical College, New York, United States
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18
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Kuba K, Yamaguchi T, Penninger JM. Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19. Front Immunol 2022; 12:732690. [PMID: 35003058 PMCID: PMC8727358 DOI: 10.3389/fimmu.2021.732690] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 12/01/2021] [Indexed: 12/20/2022] Open
Abstract
Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.
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Affiliation(s)
- Keiji Kuba
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan
| | - Tomokazu Yamaguchi
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan
| | - Josef M Penninger
- Institute of Molecular Biotechnology Austria (IMBA), Vienna, Austria.,Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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19
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SARS-CoV-2 spike engagement of ACE2 primes S2' site cleavage and fusion initiation. Proc Natl Acad Sci U S A 2022; 119:2111199119. [PMID: 34930824 PMCID: PMC8740742 DOI: 10.1073/pnas.2111199119] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2021] [Indexed: 01/10/2023] Open
Abstract
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in tremendous loss worldwide. Although viral spike (S) protein binding of angiotensin-converting enzyme 2 (ACE2) has been established, the functional consequences of the initial receptor binding and the stepwise fusion process are not clear. By utilizing a cell-cell fusion system, in complement with a pseudoviral infection model, we found that the spike engagement of ACE2 primed the generation of S2' fragments in target cells, a key proteolytic event coupled with spike-mediated membrane fusion. Mutagenesis of an S2' cleavage site at the arginine (R) 815, but not an S2 cleavage site at arginine 685, was sufficient to prevent subsequent syncytia formation and infection in a variety of cell lines and primary cells isolated from human ACE2 knock-in mice. The requirement for S2' cleavage at the R815 site was also broadly shared by other SARS-CoV-2 spike variants, such as the Alpha, Beta, and Delta variants of concern. Thus, our study highlights an essential role for host receptor engagement and the key residue of spike for proteolytic activation, and uncovers a targetable mechanism for host cell infection by SARS-CoV-2.
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20
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Sengupta S, Addya S, Biswas D, Banerjee P, Sarma JD. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in murine β-coronavirus-induced neuroinflammation. Virology 2022; 566:122-135. [PMID: 34906793 PMCID: PMC8648396 DOI: 10.1016/j.virol.2021.11.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 11/16/2021] [Accepted: 11/26/2021] [Indexed: 01/17/2023]
Abstract
Mouse hepatitis virus (MHV; m-β-CoV) serves as a useful model for studying the cellular factors involved in neuroinflammation. To understand the role of matrix metalloproteinases (MMPs) in neuroinflammation, brain tissues from m-β-CoV-infected mice were harvested at different days post-infection (d.p.i) and investigated for Mmp expression by RT-qPCR. Mmp-2, -3, -8, -12 showed significant mRNA upregulation peaking with viral replication between 5 and 6 d.p.i. Elevated levels of MMP regulator TIMP-1 are suggestive of a TIMP-1 mediated host antiviral response. Biological network assessment suggested a direct involvement of MMP-3, -8, -14 in facilitating peripheral leukocyte infiltrations. Flow cytometry confirmed the increased presence of NK cells, CD4+ and CD8+ T cells, neutrophils, and MHCII expressing cells in the m-β-CoV infected mice brain. Our study revealed that m-β-CoV upregulated Park7, RelA, Nrf2, and Hmox1 transcripts involved in ROS production and antioxidant pathways, describing the possible nexus between oxidative pathways, MMPs, and TIMP in m-β-CoV-induced neuroinflammation.
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Affiliation(s)
- Sourodip Sengupta
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata (IISER-K), Mohanpur, India
| | - Sankar Addya
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA
| | - Diptomit Biswas
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata (IISER-K), Mohanpur, India
| | - Paromita Banerjee
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata (IISER-K), Mohanpur, India
| | - Jayasri Das Sarma
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata (IISER-K), Mohanpur, India,Corresponding author
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21
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Patients with COVID-19: in the dark-NETs of neutrophils. Cell Death Differ 2021; 28:3125-3139. [PMID: 34031543 PMCID: PMC8142290 DOI: 10.1038/s41418-021-00805-z] [Citation(s) in RCA: 196] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023] Open
Abstract
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
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22
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Saadi F, Pal D, Sarma JD. Spike Glycoprotein Is Central to Coronavirus Pathogenesis-Parallel Between m-CoV and SARS-CoV-2. Ann Neurosci 2021; 28:201-218. [PMID: 35341224 PMCID: PMC8948335 DOI: 10.1177/09727531211023755] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 03/24/2021] [Indexed: 01/04/2023] Open
Abstract
Coronaviruses (CoVs) are single-stranded, polyadenylated, enveloped RNA of positive polarity with a unique potential to alter host tropism. This has been exceptionally demonstrated by the emergence of deadly virus outbreaks of the past: Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and Middle East Respiratory Syndrome (MERS-CoV) in 2012. The 2019 outbreak by the new cross-species transmission of SARS-CoV-2 has put the world on alert. CoV infection is triggered by receptor recognition, membrane fusion, and successive viral entry mediated by the surface Spike (S) glycoprotein. S protein is one of the major antigenic determinants and the target for neutralizing antibodies. It is a valuable target in antiviral therapies because of its central role in cell-cell fusion, viral antigen spread, and host immune responses leading to immunopathogenesis. The receptor-binding domain of S protein has received greater attention as it initiates host attachment and contains major antigenic determinants. However, investigating the therapeutic potential of fusion peptide as a part of the fusion core complex assembled by the heptad repeats 1 and 2 (HR1 and HR2) is also warranted. Along with receptor attachment and entry, fusion mechanisms should also be explored for designing inhibitors as a therapeutic intervention. In this article, we review the S protein function and its role in mediating membrane fusion, spread, tropism, and its associated pathogenesis with notable therapeutic strategies focusing on results obtained from studies on a murine β-Coronavirus (m-CoV) and its associated disease process.
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Affiliation(s)
- Fareeha Saadi
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Kolkata, West Bengal, India
| | - Debnath Pal
- Department of Computational and Data Sciences, Indian Institute of Science, Bengaluru, Karnataka, India
| | - Jayasri Das Sarma
- Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, Kolkata, West Bengal, India
- Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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23
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A Fragile Balance: Does Neutrophil Extracellular Trap Formation Drive Pulmonary Disease Progression? Cells 2021; 10:cells10081932. [PMID: 34440701 PMCID: PMC8394734 DOI: 10.3390/cells10081932] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/22/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022] Open
Abstract
Neutrophils act as the first line of defense during infection and inflammation. Once activated, they are able to fulfil numerous tasks to fight inflammatory insults while keeping a balanced immune response. Besides well-known functions, such as phagocytosis and degranulation, neutrophils are also able to release "neutrophil extracellular traps" (NETs). In response to most stimuli, the neutrophils release decondensed chromatin in a NADPH oxidase-dependent manner decorated with histones and granule proteins, such as neutrophil elastase, myeloperoxidase, and cathelicidins. Although primarily supposed to prevent microbial dissemination and fight infections, there is increasing evidence that an overwhelming NET response correlates with poor outcome in many diseases. Lung-related diseases especially, such as bacterial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease, aspergillosis, influenza, and COVID-19, are often affected by massive NET formation. Highly vascularized areas as in the lung are susceptible to immunothrombotic events promoted by chromatin fibers. Keeping this fragile equilibrium seems to be the key for an appropriate immune response. Therapies targeting dysregulated NET formation might positively influence many disease progressions. This review highlights recent findings on the pathophysiological influence of NET formation in different bacterial, viral, and non-infectious lung diseases and summarizes medical treatment strategies.
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24
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Rawat S, Vrati S, Banerjee A. Neutrophils at the crossroads of acute viral infections and severity. Mol Aspects Med 2021; 81:100996. [PMID: 34284874 PMCID: PMC8286244 DOI: 10.1016/j.mam.2021.100996] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/22/2022]
Abstract
Neutrophils are versatile immune effector cells essential for mounting a first-line defense against invading pathogens. However, uncontrolled activation can lead to severe life-threatening complications. Neutrophils exist as a heterogeneous population, and their interaction with pathogens and other immune cells may shape the outcome of the host immune response. Diverse classes of viruses, including the recently identified novel SARS-CoV-2, have shown to alter the various aspects of neutrophil biology, offering possibilities for selective intervention. Here, we review heterogeneity within the neutrophil population, highlighting the functional consequences of circulating phenotypes and their critical involvement in exaggerating protective and pathological immune responses against the viruses. We discuss the recent findings of neutrophil extracellular traps (NETs) in COVID-19 pathology and cover other viruses, where neutrophil biology and NETs are crucial for developing disease severity. In the end, we have also pointed out the areas where neutrophil-mediated responses can be finely tuned to outline opportunities for therapeutic manipulation in controlling inflammation against viral infection.
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Affiliation(s)
- Surender Rawat
- Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - Sudhanshu Vrati
- Regional Centre for Biotechnology, Faridabad, Haryana, India
| | - Arup Banerjee
- Regional Centre for Biotechnology, Faridabad, Haryana, India.
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25
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Barrett CT, Neal HE, Edmonds K, Moncman CL, Thompson R, Branttie JM, Boggs KB, Wu CY, Leung DW, Dutch RE. Effect of clinical isolate or cleavage site mutations in the SARS-CoV-2 spike protein on protein stability, cleavage, and cell-cell fusion. J Biol Chem 2021; 297:100902. [PMID: 34157282 PMCID: PMC8214756 DOI: 10.1016/j.jbc.2021.100902] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 06/08/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022] Open
Abstract
The trimeric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) is the sole viral protein responsible for both viral binding to a host cell and the membrane fusion event needed for cell entry. In addition to facilitating fusion needed for viral entry, S can also drive cell-cell fusion, a pathogenic effect observed in the lungs of SARS-CoV-2-infected patients. While several studies have investigated S requirements involved in viral particle entry, examination of S stability and factors involved in S cell-cell fusion remain limited. A furin cleavage site at the border between the S1 and S2 subunits (S1/S2) has been identified, along with putative cathepsin L and transmembrane serine protease 2 cleavage sites within S2. We demonstrate that S must be processed at the S1/S2 border in order to mediate cell-cell fusion and that mutations at potential cleavage sites within the S2 subunit alter S processing at the S1/S2 border, thus preventing cell-cell fusion. We also identify residues within the internal fusion peptide and the cytoplasmic tail that modulate S-mediated cell-cell fusion. In addition, we examined S stability and protein cleavage kinetics in a variety of mammalian cell lines, including a bat cell line related to the likely reservoir species for SARS-CoV-2, and provide evidence that proteolytic processing alters the stability of the S trimer. This work therefore offers insight into S stability, proteolytic processing, and factors that mediate S cell-cell fusion, all of which help give a more comprehensive understanding of this high-profile therapeutic target.
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Affiliation(s)
- Chelsea T Barrett
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Hadley E Neal
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Kearstin Edmonds
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Carole L Moncman
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Rachel Thompson
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Jean M Branttie
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Kerri Beth Boggs
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Cheng-Yu Wu
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Daisy W Leung
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri, USA
| | - Rebecca E Dutch
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA.
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26
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Seidah NG, Pasquato A, Andréo U. How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread? Viruses 2021; 13:v13071229. [PMID: 34202098 PMCID: PMC8310232 DOI: 10.3390/v13071229] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/09/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022] Open
Abstract
Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.
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Affiliation(s)
- Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute, University of Montreal, Montreal, QC H2W1R7, Canada;
- Correspondence: ; Tel.: +1-514-987-5609
| | - Antonella Pasquato
- Antonella Pasquato, Department of Industrial Engineering, University of Padova, Via Marzolo 9, 35131 Padova, Italy;
| | - Ursula Andréo
- Laboratory of Biochemical Neuroendocrinology Montreal Clinical Research Institute, University of Montreal, Montreal, QC H2W1R7, Canada;
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Megyeri K, Dernovics Á, Al-Luhaibi ZII, Rosztóczy A. COVID-19-associated diarrhea. World J Gastroenterol 2021; 27:3208-3222. [PMID: 34163106 PMCID: PMC8218355 DOI: 10.3748/wjg.v27.i23.3208] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/19/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as a highly virulent respiratory pathogen that is known as the causative agent of coronavirus disease 2019 (COVID-19). Diarrhea is a common early symptom in a significant proportion of patients with SARS-CoV-2 infection. SARS-CoV-2 can infect and replicate in esophageal cells and enterocytes, leading to direct damage to the intestinal epithelium. The infection decreases the level of angiotensin-converting enzyme 2 receptors, thereby altering the composition of the gut microbiota. SARS-CoV-2 elicits a cytokine storm, which contributes to gastrointestinal inflammation. The direct cytopathic effects of SARS-CoV-2, gut dysbiosis, and aberrant immune response result in increased intestinal permeability, which may exacerbate existing symptoms and worsen the prognosis. By exploring the elements of pathogenesis, several therapeutic options have emerged for the treatment of COVID-19 patients, such as biologics and biotherapeutic agents. However, the presence of SARS-CoV-2 in the feces may facilitate the spread of COVID-19 through fecal-oral transmission and contaminate the environment. Thus gastrointestinal SARS-CoV-2 infection has important epidemiological significance. The development of new therapeutic and preventive options is necessary to treat and restrict the spread of this severe and widespread infection more effectively. Therefore, we summarize the key elements involved in the pathogenesis and the epidemiology of COVID-19-associated diarrhea.
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Affiliation(s)
- Klara Megyeri
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - Zaid I I Al-Luhaibi
- Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged 6720, Csongrad, Hungary
| | - András Rosztóczy
- Division of Gastroenterology, Department of Internal Medicine, University of Szeged, Szeged 6720, Csongrad, Hungary
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28
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Zhang Q, Xiang R, Huo S, Zhou Y, Jiang S, Wang Q, Yu F. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Signal Transduct Target Ther 2021; 6:233. [PMID: 34117216 PMCID: PMC8193598 DOI: 10.1038/s41392-021-00653-w] [Citation(s) in RCA: 204] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/30/2021] [Accepted: 05/10/2021] [Indexed: 02/05/2023] Open
Abstract
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 has an exceptionally high level of transmissibility and extremely broad tissue tropism. However, the underlying molecular mechanism responsible for sustaining this degree of virulence remains largely unexplored. In this article, we review the current knowledge and crucial information about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors, such as ACE2, neuropilin-1, AXL, and antibody-FcγR complexes. We further explain how its spike (S) protein undergoes conformational transition from prefusion to postfusion with the help of proteases like furin, TMPRSS2, and cathepsins. We then review the ongoing experimental studies and clinical trials of antibodies, peptides, or small-molecule compounds with anti-SARS-CoV-2 activity, and discuss how these antiviral therapies targeting host-pathogen interaction could potentially suppress viral attachment, reduce the exposure of fusion peptide to curtail membrane fusion and block the formation of six-helix bundle (6-HB) fusion core. Finally, the specter of rapidly emerging SARS-CoV-2 variants deserves a serious review of broad-spectrum drugs or vaccines for long-term prevention and control of COVID-19 in the future.
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Affiliation(s)
- Qianqian Zhang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Rong Xiang
- College of Life Sciences, Hebei Agricultural University, Baoding, China
| | - Shanshan Huo
- College of Life Sciences, Hebei Agricultural University, Baoding, China
| | - Yunjiao Zhou
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China
| | - Shibo Jiang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
| | - Qiao Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China.
| | - Fei Yu
- College of Life Sciences, Hebei Agricultural University, Baoding, China.
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29
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Hazeldine J, Lord JM. Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets. Front Immunol 2021; 12:680134. [PMID: 34149717 PMCID: PMC8206563 DOI: 10.3389/fimmu.2021.680134] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/17/2021] [Indexed: 01/08/2023] Open
Abstract
Whilst the majority of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, experience mild to moderate symptoms, approximately 20% develop severe respiratory complications that may progress to acute respiratory distress syndrome, pulmonary failure and death. To date, single cell and high-throughput systems based analyses of the peripheral and pulmonary immune responses to SARS-CoV-2 suggest that a hyperactive and dysregulated immune response underpins the development of severe disease, with a prominent role assigned to neutrophils. Characterised in part by robust generation of neutrophil extracellular traps (NETs), the presence of immature, immunosuppressive and activated neutrophil subsets in the circulation, and neutrophilic infiltrates in the lung, a granulocytic signature is emerging as a defining feature of severe COVID-19. Furthermore, an assessment of the number, maturity status and/or function of circulating neutrophils at the time of hospital admission has shown promise as a prognostic tool for the early identification of patients at risk of clinical deterioration. Here, by summarising the results of studies that have examined the peripheral and pulmonary immune response to SARS-CoV-2, we provide a comprehensive overview of the changes that occur in the composition, phenotype and function of the neutrophil pool in COVID-19 patients of differing disease severities and discuss potential mediators of SARS-CoV-2-induced neutrophil dysfunction. With few specific treatments currently approved for COVID-19, we conclude the review by discussing whether neutrophils represent a potential therapeutic target for the treatment of patients with severe COVID-19.
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Affiliation(s)
- Jon Hazeldine
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
- National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Janet M. Lord
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
- National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospital Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, United Kingdom
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30
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Raghav PK, Kalyanaraman K, Kumar D. Human cell receptors: potential drug targets to combat COVID-19. Amino Acids 2021; 53:813-842. [PMID: 33950300 PMCID: PMC8097256 DOI: 10.1007/s00726-021-02991-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 04/21/2021] [Indexed: 01/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19). The World Health Organization (WHO) has announced that COVID-19 is a pandemic having a higher spread rate rather than the mortality. Identification of a potential approach or therapy against COVID-19 is still under consideration. Therefore, it is essential to have an insight into SARS-CoV-2, its interacting partner, and domains for an effective treatment. The present study is divided into three main categories, including SARS-CoV-2 prominent receptor and its expression levels, other interacting partners, and their binding domains. The first section focuses primarily on coronaviruses' general aspects (SARS-CoV-2, SARS-CoV, and the Middle East Respiratory Syndrome Coronaviruses (MERS-CoV)) their structures, similarities, and mode of infections. The second section discusses the host receptors which includes the human targets of coronaviruses like dipeptidyl peptidase 4 (DPP4), CD147, CD209L, Angiotensin-Converting Enzyme 2 (ACE2), and other miscellaneous targets (type-II transmembrane serine proteases (TTSPs), furin, trypsin, cathepsins, thermolysin, elastase, phosphatidylinositol 3-phosphate 5-kinase, two-pore segment channel, and epithelium sodium channel C-α subunit). The human cell receptor, ACE2 plays an essential role in the Renin-Angiotensin system (RAS) pathway and COVID-19. Thus, this section also discusses the ACE2 expression and risk of COVID-19 infectivity in various organs and tissues such as the liver, lungs, intestine, heart, and reproductive system in the human body. Absence of ACE2 protein expression in immune cells could be used for limiting the SARS-CoV-2 infection. The third section covers the current available approaches for COVID-19 treatment. Overall, this review focuses on the critical role of human cell receptors involved in coronavirus pathogenesis, which would likely be used in designing target-specific drugs to combat COVID-19.
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Affiliation(s)
| | - Keerthana Kalyanaraman
- Amity Institute of Biotechnology, Amity University, Sector-125, Noida, Uttar Pradesh, India
| | - Dinesh Kumar
- ICMR-National Institute of Cancer Prevention & Research, Noida, 201301, India.
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31
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Abstract
The high SARS-CoV-2 reproductive number driving the COVID-19 pandemic has been a mystery. Our recent in vitro, and in vivo coronaviral pathogenesis studies involving Mouse Hepatitis Virus (MHV-A59) suggest a crucial role for a small host membrane-virus contact initiator region of the Spike protein, called the fusion peptide that enhances the virus fusogenicity and infectivity. Here I study the Spike from five human β-coronaviruses (HCoV) including the SARS-CoV-2, and MHV-A59 for comparison. The structural and dynamics analyses of the Spike show that its fusion loop spatially organizes three fusion peptides contiguous to each other to synergistically trigger the virus-host membrane fusion process. I propose a Contact Initiation Model based on the architecture of the Spike quaternary structure that explains the obligatory participation of the fusion loop in the initiation of the host membrane contact for the virus fusion process. Among all the HCoV Spikes in this study, SARS-CoV-2 has the most hydrophobic surface and the extent of hydrophobicity correlates with the reproductive number and infectivity of the other HCoV. Comparison between results from standard and replica exchange molecular dynamics reveal the unique physicochemical properties of the SARS-CoV-2 fusion peptides, accrued in part from the presence of consecutive prolines that impart backbone rigidity which aids the virus fusogenicity. The priming of the Spike by its cleavage and subsequent fusogenic conformational transition steered by the fusion loop may be critical for the SARS-CoV-2 spread. The importance of the fusion loop makes it an apt target for anti-virals and vaccine candidates.
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Affiliation(s)
- Debnath Pal
- Indian Institute of Science, Bengaluru 560012, India.
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32
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Bhattacharyya C, Das C, Ghosh A, Singh AK, Mukherjee S, Majumder PP, Basu A, Biswas NK. SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2021; 90:104760. [PMID: 33556558 PMCID: PMC7863758 DOI: 10.1016/j.meegid.2021.104760] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/01/2021] [Accepted: 02/03/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 was first reported from China. Within three months, it evolved to 10 additional subtypes. Two evolved subtypes (A2 and A2a) carry a non-synonymous Spike protein mutation (D614G). We conducted phylodynamic analysis of over 70,000 SARS-CoV-2 coronaviruses worldwide, sequenced until July2020, and found that the mutant subtype (614G) outcompeted the pre-existing type (614D), significantly faster in Europe and North-America than in East Asia. Bioinformatically and computationally, we identified a novel neutrophil elastase (ELANE) cleavage site introduced in the G-mutant, near the S1-S2 junction of the Spike protein. We hypothesised that elevation of neutrophil elastase level at the site of infection will enhance the activation of Spike protein thus facilitating host cell entry for 614G, but not the 614D, subtype. The level of neutrophil elastase in the lung is modulated by its inhibitor α1-antitrypsin (AAT). AAT prevents lung tissue damage by elastase. However, many individuals exhibit genotype-dependent deficiency of AAT. AAT deficiency eases host-cell entry of the 614G virus, by retarding inhibition of neutrophil elastase and consequently enhancing activation of the Spike protein. AAT deficiency is highly prevalent in European and North-American populations, but much less so in East Asia. Therefore, the 614G subtype is able to infect and spread more easily in populations of the former regions than in the latter region. Our analyses provide a molecular biological and evolutionary model for the higher observed virulence of the 614G subtype, in terms of causing higher morbidity in the host (higher infectivity and higher viral load), than the non-mutant 614D subtype.
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Affiliation(s)
| | - Chitrarpita Das
- National Institute of Biomedical Genomics, Kalyani 741251, India
| | - Arnab Ghosh
- National Institute of Biomedical Genomics, Kalyani 741251, India
| | - Animesh K. Singh
- National Institute of Biomedical Genomics, Kalyani 741251, India
| | - Souvik Mukherjee
- National Institute of Biomedical Genomics, Kalyani 741251, India
| | - Partha P. Majumder
- National Institute of Biomedical Genomics, Kalyani 741251, India,Indian Statistical Institute, Kolkata 700108, India
| | - Analabha Basu
- National Institute of Biomedical Genomics, Kalyani 741251, India
| | - Nidhan K. Biswas
- National Institute of Biomedical Genomics, Kalyani 741251, India,Corresponding author at: National Institute of Biomedical Genomics, P.O.: N.S.S., Kalyani 741251, West Bengal, India
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33
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Alfarouk KO, AlHoufie STS, Ahmed SBM, Shabana M, Ahmed A, Alqahtani SS, Alqahtani AS, Alqahtani AM, Ramadan AM, Ahmed ME, Ali HS, Bashir A, Devesa J, Cardone RA, Ibrahim ME, Schwartz L, Reshkin SJ. Pathogenesis and Management of COVID-19. J Xenobiot 2021; 11:77-93. [PMID: 34063739 PMCID: PMC8163157 DOI: 10.3390/jox11020006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 12/13/2022] Open
Abstract
COVID-19, occurring due to SARS-COV-2 infection, is the most recent pandemic disease that has led to three million deaths at the time of writing. A great deal of effort has been directed towards altering the virus trajectory and/or managing the interactions of the virus with its subsequent targets in the human body; these interactions can lead to a chain reaction-like state manifested by a cytokine storm and progress to multiple organ failure. During cytokine storms the ratio of pro-inflammatory to anti-inflammatory mediators is generally increased, which contributes to the instigation of hyper-inflammation and confers advantages to the virus. Because cytokine expression patterns fluctuate from one person to another and even within the same person from one time to another, we suggest a road map of COVID-19 management using an individual approach instead of focusing on the blockbuster process (one treatment for most people, if not all). Here, we highlight the biology of the virus, study the interaction between the virus and humans, and present potential pharmacological and non-pharmacological modulators that might contribute to the global war against SARS-COV-2. We suggest an algorithmic roadmap to manage COVID-19.
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Affiliation(s)
- Khalid O. Alfarouk
- Hala Alfarouk Cancer Center, Department of Evolutionary Pharmacology and Tumor Metabolism, Khartoum 11123, Sudan;
- Research Center, Zamzam University College, Khartoum 11123, Sudan;
| | - Sari T. S. AlHoufie
- Medical Laboratories Technology Department, College of Applied Medical Sciences, Taibah University, Medina 42353, Saudi Arabia;
| | - Samrein B. M. Ahmed
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;
| | - Mona Shabana
- Pharmacology Department, Faculty of Medicine, Fayoum University, Fayoum 63514, Egypt;
| | - Ahmed Ahmed
- Department of Oesphogastric and General Surgery, University Hospitals of Leicester, Leicester LE5 4PW, UK;
| | - Saad S. Alqahtani
- Pharmacy Practice Research Unit, Clinical Pharmacy Department, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Ali S. Alqahtani
- Department of Medical Laboratories Sciences, College of Applied Medical Sciences, Najran University, Najran 66446, Saudi Arabia;
| | - Ali M. Alqahtani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia;
| | - AbdelRahman M. Ramadan
- Department of Preventive Dental Sciences, Ibn Sina National College, Jeddah 22421, Saudi Arabia;
| | - Mohamed E. Ahmed
- Research Center, Zamzam University College, Khartoum 11123, Sudan;
- Department of Surgery, Faculty of Medicine Al-Neelain University, Khartoum 11111, Sudan
| | - Heyam S. Ali
- Faculty of Pharmacy, University of Khartoum, P. O. Box 321, Khartoum 11111, Sudan;
| | - Adil Bashir
- Hala Alfarouk Cancer Center, Department of Evolutionary Pharmacology and Tumor Metabolism, Khartoum 11123, Sudan;
- Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan;
| | - Jesus Devesa
- Scientific Direction, Foltra Medical Centre, 15886 Teo, Spain;
| | - Rosa A. Cardone
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (R.A.C.); (S.J.R.)
| | - Muntaser E. Ibrahim
- Institute of Endemic Diseases, University of Khartoum, Khartoum 11111, Sudan;
| | | | - Stephan J. Reshkin
- Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70126 Bari, Italy; (R.A.C.); (S.J.R.)
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You J, Seok JH, Joo M, Bae JY, Kim JI, Park MS, Kim K. Multifactorial Traits of SARS-CoV-2 Cell Entry Related to Diverse Host Proteases and Proteins. Biomol Ther (Seoul) 2021; 29:249-262. [PMID: 33875625 PMCID: PMC8094071 DOI: 10.4062/biomolther.2021.048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 11/05/2022] Open
Abstract
The most effective way to control newly emerging infectious disease, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, is to strengthen preventative or therapeutic public health strategies before the infection spreads worldwide. However, global health systems remain at the early stages in anticipating effective therapeutics or vaccines to combat the SARS-CoV-2 pandemic. While maintaining social distance is the most crucial metric to avoid spreading the virus, symptomatic therapy given to patients on the clinical manifestations helps save lives. The molecular properties of SARS-CoV-2 infection have been quickly elucidated, paving the way to therapeutics, vaccine development, and other medical interventions. Despite this progress, the detailed biomolecular mechanism of SARS-CoV-2 infection remains elusive. Given virus invasion of cells is a determining factor for virulence, understanding the viral entry process can be a mainstay in controlling newly emerged viruses. Since viral entry is mediated by selective cellular proteases or proteins associated with receptors, identification and functional analysis of these proteins could provide a way to disrupt virus propagation. This review comprehensively discusses cellular machinery necessary for SARS-CoV-2 infection. Understanding multifactorial traits of the virus entry will provide a substantial guide to facilitate antiviral drug development.
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Affiliation(s)
- Jaehwan You
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Jong Hyeon Seok
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Myungsoo Joo
- School of Korean Medicine, Pusan National University, Pusan 50612, Republic of Korea
| | - Joon-Yong Bae
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Jin Il Kim
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Biosafety Center, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Man-Seong Park
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Biosafety Center, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Kisoon Kim
- Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea
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35
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α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome? Anesthesiology 2021; 134:792-808. [PMID: 33721888 DOI: 10.1097/aln.0000000000003727] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.
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36
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Arena ME, Alberto MR, Cartagena E. Potential use of Citrus essential oils against acute respiratory syndrome caused by coronavirus. JOURNAL OF ESSENTIAL OIL RESEARCH 2021. [DOI: 10.1080/10412905.2021.1912839] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Mario Eduardo Arena
- Instituto de Biotecnología Farmacéutica y Alimentaria (INBIOFAL) CONICET–UNT, Tucumán, Argentina
- Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán (UNT), Tucumán, Argentina
| | - María Rosa Alberto
- Instituto de Biotecnología Farmacéutica y Alimentaria (INBIOFAL) CONICET–UNT, Tucumán, Argentina
- Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán (UNT), Tucumán, Argentina
| | - Elena Cartagena
- Instituto de Biotecnología Farmacéutica y Alimentaria (INBIOFAL) CONICET–UNT, Tucumán, Argentina
- Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán (UNT), Tucumán, Argentina
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37
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Rodriguez T, Dobrovolny HM. Quantifying the effect of trypsin and elastase on in vitro SARS-CoV infections. Virus Res 2021; 299:198423. [PMID: 33845063 PMCID: PMC8043718 DOI: 10.1016/j.virusres.2021.198423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/29/2021] [Accepted: 04/01/2021] [Indexed: 11/24/2022]
Abstract
The SARS coronavirus (SARS-CoV) has the potential to cause serious disease that can spread rapidly around the world. Much of our understanding of SARS-CoV pathogenesis comes from in vitro experiments. Unfortunately, in vitro experiments cannot replicate all the complexity of the in vivo infection. For example, proteases in the respiratory tract cleave the SARS-CoV surface protein to facilitate viral entry, but these proteases are not present in vitro. Unfortunately, proteases might also have an effect on other parts of the replication cycle. Here, we use mathematical modeling to estimate parameters characterizing viral replication for SARS-CoV in the presence of trypsin or elastase, and in the absence of either. In addition to increasing the infection rate, the addition of trypsin and elastase causes lengthening of the eclipse phase duration and the infectious cell lifespan.
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Affiliation(s)
- Thalia Rodriguez
- Department of Physics and Astronomy, Texas Christian University, Fort Worth, TX, United States
| | - Hana M Dobrovolny
- Department of Physics and Astronomy, Texas Christian University, Fort Worth, TX, United States.
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38
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Derakhshan MA, Amani A, Faridi-Majidi R. State-of-the-Art of Nanodiagnostics and Nanotherapeutics against SARS-CoV-2. ACS APPLIED MATERIALS & INTERFACES 2021; 13:14816-14843. [PMID: 33779135 PMCID: PMC8028022 DOI: 10.1021/acsami.0c22381] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/17/2021] [Indexed: 05/02/2023]
Abstract
The pandemic outbreak of SARS-CoV-2, with millions of infected patients worldwide, has severely challenged all aspects of public health. In this regard, early and rapid detection of infected cases and providing effective therapeutics against the virus are in urgent demand. Along with conventional clinical protocols, nanomaterial-based diagnostics and therapeutics hold a great potential against coronavirus disease 2019 (COVID-19). Indeed, nanoparticles with their outstanding characteristics would render additional advantages to the current approaches for rapid and accurate diagnosis and also developing prophylactic vaccines or antiviral therapeutics. In this review, besides presenting an overview of the coronaviruses and SARS-CoV-2, we discuss the introduced nanomaterial-based detection assays and devices and also antiviral formulations and vaccines for coronaviruses.
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Affiliation(s)
- Mohammad Ali Derakhshan
- Department
of Medical Nanotechnology, School of Advanced Medical Sciences and
Technologies, Shiraz University of Medical
Sciences, Shiraz, Iran
- Nanomedicine
and Nanobiology Research Center, Shiraz
University of Medical Sciences, Shiraz Iran
| | - Amir Amani
- Natural
Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Reza Faridi-Majidi
- Department
of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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39
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Kastenhuber ER, Jaimes JA, Johnson JL, Mercadante M, Muecksch F, Weisblum Y, Bram Y, Schwartz RE, Whittaker GR, Cantley LC. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021. [PMID: 33821268 DOI: 10.1101/2021.03.31.437960] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Coagulopathy is recognized as a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. Other host proteases, including TMPRSS2, are recognized to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing viral entry. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases as well as coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.
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40
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Whittaker GR, Daniel S, Millet JK. Coronavirus entry: how we arrived at SARS-CoV-2. Curr Opin Virol 2021; 47:113-120. [PMID: 33744490 PMCID: PMC7942143 DOI: 10.1016/j.coviro.2021.02.006] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/08/2021] [Accepted: 02/25/2021] [Indexed: 01/12/2023]
Abstract
Because of the COVID-19 pandemic, the novel coronavirus SARS-CoV-2 has risen to shape scientific research during 2020, with its spike (S) protein being a predominant focus. The S protein is likely the most complicated of all viral glycoproteins and is a key factor in immunological responses and virus pathogenesis. It is also the driving force dictating virus entry mechanisms, which are highly 'plastic' for coronaviruses, allowing a plethora of options for different virus variants and strains in different cell types. Here we review coronavirus entry as a foundation for current work on SARS-CoV-2. We focus on the post-receptor binding events and cellular pathways that direct the membrane fusion events necessary for genome delivery, including S proteolytic priming and activation. We also address aspects of the entry process important for virus evolution and therapeutic development.
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Affiliation(s)
- Gary R Whittaker
- Department of Microbiology and Immunology and Master of Public Health Program, Cornell University, Ithaca, NY, USA.
| | - Susan Daniel
- Robert Frederick Smith School of Chemical & Biomolecular Engineering, Cornell University, Ithaca, NY, USA
| | - Jean K Millet
- Université Paris-Saclay, INRAE, UVSQ, Virologie et Immunologie Moléculaires, Jouy-en-Josas, France
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41
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Ujike M, Taguchi F. Recent Progress in Torovirus Molecular Biology. Viruses 2021; 13:435. [PMID: 33800523 PMCID: PMC7998386 DOI: 10.3390/v13030435] [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] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/24/2021] [Accepted: 02/24/2021] [Indexed: 11/16/2022] Open
Abstract
Torovirus (ToV) has recently been classified into the new family Tobaniviridae, although it belonged to the Coronavirus (CoV) family historically. ToVs are associated with enteric diseases in animals and humans. In contrast to CoVs, which are recognised as pathogens of veterinary and medical importance, little attention has been paid to ToVs because their infections are usually asymptomatic or not severe; for a long time, only one equine ToV could be propagated in cultured cells. However, bovine ToVs, which predominantly cause diarrhoea in calves, have been detected worldwide, leading to economic losses. Porcine ToVs have also spread globally; although they have not caused serious economic losses, coinfections with other pathogens can exacerbate their symptoms. In addition, frequent inter- or intra-recombination among ToVs can increase pathogenesis or unpredicted host adaptation. These findings have highlighted the importance of ToVs as pathogens and the need for basic ToV research. Here, we review recent progress in the study of ToV molecular biology including reverse genetics, focusing on the similarities and differences between ToVs and CoVs.
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Affiliation(s)
- Makoto Ujike
- Laboratory of Veterinary Infectious Diseases, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-8602, Japan;
- Research Center for Animal Life Science, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-8602, Japan
| | - Fumihiro Taguchi
- Laboratory of Veterinary Infectious Diseases, Faculty of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-8602, Japan;
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42
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Kaur U, Chakrabarti SS, Ojha B, Pathak BK, Singh A, Saso L, Chakrabarti S. Targeting Host Cell Proteases to Prevent SARS-CoV-2 Invasion. Curr Drug Targets 2021; 22:192-201. [PMID: 32972339 DOI: 10.2174/1389450121666200924113243] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/16/2020] [Accepted: 08/26/2020] [Indexed: 11/22/2022]
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread worldwide and caused widespread devastation. In the absence of definitive therapy, symptomatic management remains the standard of care. Repurposing of many existing drugs, including several anti-viral drugs, is being attempted to tackle the COVID-19 pandemic. However, most of them have failed to show significant benefit in clinical trials. An attractive approach may be to target host proteases involved in SARS-CoV-2 pathogenesis. The priming of the spike (S) protein of the virus by proteolytic cleavage by the transmembrane serine protease-2 (TMPRSS2) is necessary for the fusion of the virus to the host cell after it binds to its receptor angiotensin converting enzyme-2 (ACE2). There are other proteases with varying spatiotemporal locations that may be important for viral entry and subsequent replication inside the cells, and these include trypsin, furin and cathepsins. In this report, we have discussed the tentative therapeutic role of inhibitors of TMPRSS2, cathepsin, trypsin, furin, plasmin, factor X and elastase in infection caused by SARS-CoV-2. Both available evidence, as well as hypotheses, are discussed, with emphasis on drugs which are approved for other indications such as bromhexine, ammonium chloride, nafamostat, camostat, tranexamic acid, epsilon amino-caproic acid, chloroquine, ulinastatin, aprotinin and anticoagulant drugs. Simultaneously, novel compounds being tested and problems with using these agents are also discussed.
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Affiliation(s)
- Upinder Kaur
- Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Sankha Shubhra Chakrabarti
- Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Bisweswar Ojha
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| | - Bhairav Kumar Pathak
- Department of Biochemistry and Central Research Cell, MM Institute of Medical Sciences and Research, Maharishi Markandeshwar (deemed to be) University, Mullana, Ambala, Haryana, India
| | - Amit Singh
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
| | - Luciano Saso
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Sasanka Chakrabarti
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, India
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43
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Pal D. Spike protein fusion loop controls SARS-CoV-2 fusogenicity and infectivity. J Struct Biol 2021; 213:107713. [PMID: 33662570 PMCID: PMC7919542 DOI: 10.1016/j.jsb.2021.107713] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 01/30/2023]
Abstract
The high SARS-CoV-2 reproductive number driving the COVID-19 pandemic has been a mystery. Our recent in vitro, and in vivo coronaviral pathogenesis studies involving Mouse Hepatitis Virus (MHV-A59) suggest a crucial role for a small host membrane-virus contact initiator region of the Spike protein, called the fusion peptide that enhances the virus fusogenicity and infectivity. Here I study the Spike from five human β-coronaviruses (HCoV) including the SARS-CoV-2, and MHV-A59 for comparison. The structural and dynamics analyses of the Spike show that its fusion loop spatially organizes three fusion peptides contiguous to each other to synergistically trigger the virus-host membrane fusion process. I propose a Contact Initiation Model based on the architecture of the Spike quaternary structure that explains the obligatory participation of the fusion loop in the initiation of the host membrane contact for the virus fusion process. Among all the HCoV Spikes in this study, SARS-CoV-2 has the most hydrophobic surface and the extent of hydrophobicity correlates with the reproductive number and infectivity of the other HCoV. Comparison between results from standard and replica exchange molecular dynamics reveal the unique physicochemical properties of the SARS-CoV-2 fusion peptides, accrued in part from the presence of consecutive prolines that impart backbone rigidity which aids the virus fusogenicity. The priming of the Spike by its cleavage and subsequent fusogenic conformational transition steered by the fusion loop may be critical for the SARS-CoV-2 spread. The importance of the fusion loop makes it an apt target for anti-virals and vaccine candidates.
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Affiliation(s)
- Debnath Pal
- Indian Institute of Science, Bengaluru 560012, India.
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44
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Verma J, Subbarao N. A comparative study of human betacoronavirus spike proteins: structure, function and therapeutics. Arch Virol 2021; 166:697-714. [PMID: 33483791 PMCID: PMC7821988 DOI: 10.1007/s00705-021-04961-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/20/2020] [Indexed: 01/24/2023]
Abstract
Coronaviruses are the paradigm of emerging 21st century zoonotic viruses, triggering numerous outbreaks and a severe global health crisis. The current COVID-19 pandemic caused by SARS-CoV-2 has affected more than 51 million people across the globe as of 12 November 2020. The crown-like spikes on the surface of the virion are the unique structural feature of viruses in the family Coronaviridae. The spike (S) protein adopts distinct conformations while mediating entry of the virus into the host. This multifunctional protein mediates the entry process by recognizing its receptor on the host cell, followed by the fusion of the viral membrane with the host cell membrane. This review article focuses on the structural and functional comparison of S proteins of the human betacoronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we review the current state of knowledge about receptor recognition, the membrane fusion mechanism, structural epitopes, and glycosylation sites of the S proteins of these viruses. We further discuss various vaccines and other therapeutics such as monoclonal antibodies, peptides, and small molecules based on the S protein of these three viruses.
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Affiliation(s)
- Jyoti Verma
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Naidu Subbarao
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
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45
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El‐Shimy IA, Mohamed MMA, Hasan SS, Hadi MA. Targeting host cell proteases as a potential treatment strategy to limit the spread of SARS-CoV-2 in the respiratory tract. Pharmacol Res Perspect 2021; 9:e00698. [PMID: 33369210 PMCID: PMC7758277 DOI: 10.1002/prp2.698] [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: 07/19/2020] [Revised: 09/24/2020] [Accepted: 11/13/2020] [Indexed: 12/15/2022] Open
Abstract
As the death toll of Coronavirus disease 19 (COVID-19) continues to rise worldwide, it is imperative to explore novel molecular mechanisms for targeting SARS-CoV-2. Rather than looking for drugs that directly interact with key viral proteins inhibiting its replication, an alternative and possibly add-on approach is to dismantle the host cell machinery that enables the virus to infect the host cell and spread from one cell to another. Excellent examples of such machinery are host cell proteases whose role in viral pathogenesis has been demonstrated in numerous coronaviruses. In this review, we propose two therapeutic modalities to tackle SARS-CoV-2 infections; the first is to transcriptionally modulate the expression of cellular proteases and their endogenous inhibitors and the second is to directly inhibit their enzymatic activity. We present a nonexhaustive collection of clinically investigated drugs that act by one of these mechanisms and thus represent promising candidates for preclinical in vitro testing and hopefully clinical testing in COVID-19 patients.
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Affiliation(s)
- Ismail A. El‐Shimy
- Integrative Research Institute (IRI) for Life SciencesHumboldt University BerlinBerlinGermany
- Institute of PathologyCharité ‐ Universitätsmedizin BerlinBerlinGermany
| | | | | | - Muhammad A. Hadi
- School of PharmacyCollege of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
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46
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Domon H, Maekawa T, Isono T, Furuta K, Kaito C, Terao Y. Proteolytic cleavage of HLA class II by human neutrophil elastase in pneumococcal pneumonia. Sci Rep 2021; 11:2432. [PMID: 33510372 PMCID: PMC7843615 DOI: 10.1038/s41598-021-82212-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/18/2021] [Indexed: 12/21/2022] Open
Abstract
Bacterial and viral respiratory infections can initiate acute lung injury and acute respiratory distress syndrome. Neutrophils and their granule enzymes, including neutrophil elastase, are key mediators of the pathophysiology of acute respiratory failure. Although intracellular neutrophil elastase functions as a host defensive factor against pathogens, its leakage into airway spaces induces degradation of host connective tissue components. This leakage disrupts host innate immune responses via proteolytic cleavage of Toll-like receptors and cytokines. Here, we investigated whether neutrophils possess proteases that cleave adaptive immune molecules. We found that expression of the human leukocyte antigen (HLA) class II molecule HLA-DP β1 was decreased in THP-1-derived macrophages treated with supernatants from dead neutrophils. This decreased HLA-DP β1 expression was counteracted by treatment with neutrophil elastase inhibitor, suggesting proteolytic cleavage of HLA-DP β1 by neutrophil elastase. SDS-PAGE showed that neutrophil elastase cleaved recombinant HLA-DP α1, -DP β1, -DQ α1, -DQ β1, -DR α, and -DR β1. Neutrophil elastase also cleaved HLA-DP β1 on extracellular vesicles isolated from macrophages without triggering morphological changes. Thus, leakage of neutrophil elastase may disrupt innate immune responses, antigen presentation, and T cell activation. Additionally, inhibition of neutrophil elastase is a potential therapeutic option for treating bacterial and viral pneumonia.
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Affiliation(s)
- Hisanori Domon
- Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tomoki Maekawa
- Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshihito Isono
- Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kazuyuki Furuta
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Chikara Kaito
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yutaka Terao
- Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
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47
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Barrett CT, Neal HE, Edmonds K, Moncman CL, Thompson R, Branttie JM, Boggs KB, Wu CY, Leung DW, Dutch RE. Effect of mutations in the SARS-CoV-2 spike protein on protein stability, cleavage, and cell-cell fusion function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.01.24.428007. [PMID: 33532777 PMCID: PMC7852270 DOI: 10.1101/2021.01.24.428007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The SARS-CoV-2 spike protein (S) is the sole viral protein responsible for both viral binding to a host cell and the membrane fusion event needed for cell entry. In addition to facilitating fusion needed for viral entry, S can also drive cell-cell fusion, a pathogenic effect observed in the lungs of SARS-CoV-2 infected patients. While several studies have investigated S requirements involved in viral particle entry, examination of S stability and factors involved in S cell-cell fusion remain limited. We demonstrate that S must be processed at the S1/S2 border in order to mediate cell-cell fusion, and that mutations at potential cleavage sites within the S2 subunit alter S processing at the S1/S2 border, thus preventing cell-cell fusion. We also identify residues within the internal fusion peptide and the cytoplasmic tail that modulate S cell-cell fusion. Additionally, we examine S stability and protein cleavage kinetics in a variety of mammalian cell lines, including a bat cell line related to the likely reservoir species for SARS-CoV-2, and provide evidence that proteolytic processing alters the stability of the S trimer. This work therefore offers insight into S stability, proteolytic processing, and factors that mediate S cell-cell fusion, all of which help give a more comprehensive understanding of this highly sought-after therapeutic target.
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Affiliation(s)
- Chelsea T. Barrett
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Hadley E. Neal
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Kearstin Edmonds
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Carole L. Moncman
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Rachel Thompson
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Jean M. Branttie
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Kerri Beth Boggs
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Cheng-Yu Wu
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Daisy W. Leung
- Division of Infection Diseases, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Rebecca E. Dutch
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
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48
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SARS-CoV-2 and other human coronaviruses: Mapping of protease recognition sites, antigenic variation of spike protein and their grouping through molecular phylogenetics. INFECTION GENETICS AND EVOLUTION 2021; 89:104729. [PMID: 33497837 PMCID: PMC7826164 DOI: 10.1016/j.meegid.2021.104729] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/10/2020] [Accepted: 01/20/2021] [Indexed: 11/20/2022]
Abstract
In recent years, a total of seven human pathogenic coronaviruses (HCoVs) strains were identified, i.e., SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Here, we performed an analysis of the protease recognition sites and antigenic variation of the S-protein of these HCoVs. We showed tissue-specific expression pattern, functions, and a number of recognition sites of proteases in S-proteins from seven strains of HCoVs. In the case of SARS-CoV-2, we found two new protease recognition sites, each of calpain-2, pepsin-A, and caspase-8, and one new protease recognition site each of caspase-6, caspase-3, and furin. Our antigenic mapping study of the S-protein of these HCoVs showed that the SARS-CoV-2 virus strain has the most potent antigenic epitopes (highest antigenicity score with maximum numbers of epitope regions). Additionally, the other six strains of HCoVs show common antigenic epitopes (both B-cell and T-cell), with low antigenicity scores compared to SARS-CoV-2. We suggest that the molecular evolution of structural proteins of human CoV can be classified, such as (i) HCoV-NL63 and HCoV-229E, (ii) SARS-CoV-2, and SARS-CoV and (iii) HCoV-OC43 and HCoV-HKU1. In conclusion, we can presume that our study might help to prepare the interventions for the possible HCoVs outbreaks in the future.
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49
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Gomes CP, Fernandes DE, Casimiro F, da Mata GF, Passos MT, Varela P, Mastroianni-Kirsztajn G, Pesquero JB. Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics. Front Cell Infect Microbiol 2020; 10:589505. [PMID: 33364201 PMCID: PMC7753008 DOI: 10.3389/fcimb.2020.589505] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 11/12/2020] [Indexed: 01/08/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) is the most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by a robust immunological response leading to ARDS and multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. CatL is a lysosomal enzyme that participates in numerous physiological processes, including apoptosis, antigen processing, and extracellular matrix remodeling. CatL is implicated in pathological conditions like invasion and metastasis of tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, and other diseases. CatL expression is up-regulated during chronic inflammation and is involved in degrading extracellular matrix, an important process for SARS-CoV-2 to enter host cells. In addition, CatL is probably involved in processing SARS-CoV-2 spike protein. As its inhibition is detrimental to SARS-CoV-2 infection and possibly exit from cells during late stages of infection, CatL could have been considered a valuable therapeutic target. Therefore, we describe here some drugs already in the market with potential CatL inhibiting capacity that could be used to treat COVID-19 patients. In addition, we discuss the possible role of host genetics in the etiology and spreading of the disease.
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Affiliation(s)
- Caio P. Gomes
- Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | - Danilo E. Fernandes
- Division of Nephrology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Fernanda Casimiro
- Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | - Gustavo F. da Mata
- Division of Nephrology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Michelle T. Passos
- Division of Nephrology, Department of Medicine, Federal University of São Paulo, São Paulo, Brazil
| | - Patricia Varela
- Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | | | - João Bosco Pesquero
- Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
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50
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Abstract
The unprecedented pandemic of coronavirus disease 2019 (COVID-19) demands effective treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The infection of SARS-CoV-2 critically depends on diverse viral or host proteases, which mediate viral entry, viral protein maturation, as well as the pathogenesis of the viral infection. Endogenous and exogenous agents targeting for proteases have been proved to be effective toward a variety of viral infections ranging from HIV to influenza virus, suggesting protease inhibitors as a promising antiviral treatment for COVID-19. In this Review, we discuss how host and viral proteases participated in the pathogenesis of COVID-19 as well as the prospects and ongoing clinical trials of protease inhibitors as treatments.
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Affiliation(s)
- Binquan Luan
- Computational
Biological Center, IBM Thomas J. Watson
Research, Yorktown
Heights, New York 10598, United States
| | - Tien Huynh
- Computational
Biological Center, IBM Thomas J. Watson
Research, Yorktown
Heights, New York 10598, United States
| | - Xuemei Cheng
- Department
of Physics, Bryn Mawr College, Bryn Mawr, Pennsylvania 19010, United States
| | - Ganhui Lan
- Covance,
Inc., 206 Carnegie Center
Drive, Princeton, New Jersey 08540, United States
| | - Hao-Ran Wang
- Neoland
Biosciences, Medford, Massachusetts 02155, United States
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