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1.
Microbiol Spectr ; 10(2): e0216721, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1784773

ABSTRACT

The SARS-CoV-2 coronavirus, which causes COVID-19, uses a viral surface spike protein for host cell entry and the human cell-surface transmembrane serine protease, TMPRSS2, to process the spike protein. Camostat mesylate, an orally available and clinically used serine protease inhibitor, inhibits TMPRSS2, supporting clinical trials to investigate its use in COVID-19. A one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for camostat and the active metabolite FOY-251 was developed, incorporating TMPRSS2 reversible covalent inhibition by FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. The model predicts that 95% inhibition of TMPRSS2 is required for 50% inhibition of viral entry efficiency. For camostat 200 mg dosed four times daily, 90% inhibition of TMPRSS2 is predicted to occur but with only about 40% viral entry inhibition. For 3-fold higher camostat dosing, marginal improvement of viral entry rate inhibition, up to 54%, is predicted. Because respiratory tract viral load may be associated with negative outcome, even modestly reducing viral entry and respiratory tract viral load may reduce disease progression. This modeling also supports medicinal chemistry approaches to enhancing PK/PD and potency of the camostat molecule. IMPORTANCE Strategies to repurpose already-approved drugs for the treatment of COVID-19 has been attractive since the beginning of the pandemic. Camostat mesylate, a serine protease inhibitor approved in Japan for the treatment of acute exacerbations of chronic pancreatitis, inhibits TMPRSS1, a host cell surface serine protease essential for SARS-CoV-2 viral entry. In vitro experiments provided data suggesting that camostat might be effective in the treatment of COVID-19. Multiple clinical trials were planned to test the hypothesis that camostat would be beneficial for treating COVID-19 (for example, clinicaltrials.gov, NCT04353284). The present work used a one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) mathematical model for camostat and the active metabolite FOY-251, incorporating TMPRSS2 reversible covalent inhibition by FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. This work is valuable to guide further development of camostat mesylate and possible medicinal chemistry derivatives for the treatment of COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/drug therapy , Clinical Studies as Topic , Esters , Guanidines , Humans , Serine Proteases , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Spike Glycoprotein, Coronavirus
2.
Nature ; 605(7909): 340-348, 2022 05.
Article in English | MEDLINE | ID: covidwho-1764188

ABSTRACT

The COVID-19 pandemic caused by the SARS-CoV-2 virus remains a global public health crisis. Although widespread vaccination campaigns are underway, their efficacy is reduced owing to emerging variants of concern1,2. Development of host-directed therapeutics and prophylactics could limit such resistance and offer urgently needed protection against variants of concern3,4. Attractive pharmacological targets to impede viral entry include type-II transmembrane serine proteases (TTSPs) such as TMPRSS2; these proteases cleave the viral spike protein to expose the fusion peptide for cell entry, and thus have an essential role in the virus lifecycle5,6. Here we identify and characterize a small-molecule compound, N-0385, which exhibits low nanomolar potency and a selectivity index of higher than 106 in inhibiting SARS-CoV-2 infection in human lung cells and in donor-derived colonoids7. In Calu-3 cells it inhibits the entry of the SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). Notably, in the K18-human ACE2 transgenic mouse model of severe COVID-19, we found that N-0385 affords a high level of prophylactic and therapeutic benefit after multiple administrations or even after a single administration. Together, our findings show that TTSP-mediated proteolytic maturation of the spike protein is critical for SARS-CoV-2 infection in vivo, and suggest that N-0385 provides an effective early treatment option against COVID-19 and emerging SARS-CoV-2 variants of concern.


Subject(s)
COVID-19 , SARS-CoV-2 , Serine Proteinase Inhibitors , Animals , COVID-19/prevention & control , COVID-19/virology , Disease Models, Animal , Humans , Mice , Mice, Transgenic , SARS-CoV-2/drug effects , Serine Endopeptidases , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
3.
Int J Mol Sci ; 23(3)2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1650980

ABSTRACT

TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses as well. Consequently, inhibiting TMPRSS2 activity is a promising strategy to block viral infection. In this review, we provide an overview of the role of TMPRSS2 in the entry processes of different respiratory viruses. We then review the different classes of TMPRSS2 inhibitors and their clinical development, with a focus on COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , Molecular Targeted Therapy/trends , Serine Endopeptidases/physiology , COVID-19/genetics , Humans , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Virus Internalization/drug effects
4.
J Neuroinflammation ; 19(1): 8, 2022 Jan 06.
Article in English | MEDLINE | ID: covidwho-1613238

ABSTRACT

BACKGROUND: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. METHODS: CD-1 mice received an intraperitoneal injection of R848 (200 µg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 µL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. RESULTS: R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. CONCLUSIONS: Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.


Subject(s)
Benzamidines , Guanidines , Inflammation/drug therapy , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors , Toll-Like Receptor 7/immunology , Virus Diseases/drug therapy , Animals , Benzamidines/pharmacology , Benzamidines/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Guanidines/pharmacology , Guanidines/therapeutic use , Illness Behavior/drug effects , Imidazoles/administration & dosage , Imidazoles/immunology , Inflammation/metabolism , Inflammation/virology , Male , Mice , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/therapeutic use , Toll-Like Receptor 7/agonists , Virus Diseases/metabolism , Virus Diseases/virology
7.
Int J Mol Sci ; 22(13)2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1288905

ABSTRACT

Positively charged groups that mimic arginine or lysine in a natural substrate of trypsin are necessary for drugs to inhibit the trypsin-like serine protease TMPRSS2 that is involved in the viral entry and spread of coronaviruses, including SARS-CoV-2. Based on this assumption, we identified a set of 13 approved or clinically investigational drugs with positively charged guanidinobenzoyl and/or aminidinobenzoyl groups, including the experimentally verified TMPRSS2 inhibitors Camostat and Nafamostat. Molecular docking using the C-I-TASSER-predicted TMPRSS2 catalytic domain model suggested that the guanidinobenzoyl or aminidinobenzoyl group in all the drugs could form putative salt bridge interactions with the side-chain carboxyl group of Asp435 located in the S1 pocket of TMPRSS2. Molecular dynamics simulations further revealed the high stability of the putative salt bridge interactions over long-time (100 ns) simulations. The molecular mechanics/generalized Born surface area-binding free energy assessment and per-residue energy decomposition analysis also supported the strong binding interactions between TMPRSS2 and the proposed drugs. These results suggest that the proposed compounds, in addition to Camostat and Nafamostat, could be effective TMPRSS2 inhibitors for COVID-19 treatment by occupying the S1 pocket with the hallmark positively charged groups.


Subject(s)
Antiviral Agents/chemistry , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Benzamidines/chemistry , Benzamidines/metabolism , Binding Sites , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Esters/chemistry , Esters/metabolism , Guanidines/chemistry , Guanidines/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/therapeutic use , Thermodynamics
8.
Adv Exp Med Biol ; 1304: 215-226, 2021.
Article in English | MEDLINE | ID: covidwho-1237451

ABSTRACT

Lung is a vital organ that ensures breathing function. It provides the essential interface of air filtering providing oxygen to the whole body and eliminating carbon dioxide in the blood; because of its exposure to the external environment, it is fall prey to many exogenous elements, such as pathogens, especially viral infections or environmental toxins and chemicals. These exogenous actors in addition to intrinsic disorders lead to important inflammatory responses that compromise lung tissue and normal functioning. Serine proteases regulating inflammation responses are versatile enzymes, usually involved in pro-inflammatory cytokines or other molecular mediator's production and activation of immune cells. In this chapter, an overview on major serine proteases in airway inflammation as therapeutic targets and their clinically relevant inhibitors is provided. Recent updates on serine protease inhibitors in the context of the COVID-19 pandemic are summarized.


Subject(s)
COVID-19 , Serine Proteinase Inhibitors , Humans , Lung , Pandemics , SARS-CoV-2 , Serine Proteases , Serine Proteinase Inhibitors/therapeutic use
10.
Med Hypotheses ; 146: 110452, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-965499

ABSTRACT

Statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors interfere with several pathophysiological pathways of coronavirus disease 2019 (COVID-19). Statins may have a direct antiviral effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by inhibiting its main protease. Statin-induced up-regulation of angiotensin-converting enzyme 2 (ACE2) may also be beneficial, whereas cholesterol reduction might significantly suppress SARS-CoV-2 by either blocking its host-cell entry through the disruption of lipid rafts or by inhibiting its replication. Available human studies have shown beneficial effects of statins and PCSK9 inhibitors on pneumonia and sepsis. These drugs may act as immunomodulators in COVID-19 and protect against major complications, such as acute respiratory distress syndrome and cytokine release syndrome. Considering their antioxidative, anti-arrhythmic, antithrombotic properties and their beneficial effect on endothelial dysfunction, along with the increased risk of mortality of patients at high cardiovascular risk infected by SARS-CoV-2, statins and PCSK9 inhibitors might prove effective against the cardiovascular and thromboembolic complications of COVID-19. On the whole, randomized clinical trials are needed to establish routine use of statins and PCSK9 inhibitors in the treatment of SARS-CoV-2 infection. In the meantime, it is recommended that lipid-lowering therapy should not be discontinued in COVID-19 patients unless otherwise indicated.


Subject(s)
COVID-19/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Serine Proteinase Inhibitors/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/physiopathology , Cardiovascular Diseases/prevention & control , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Immunity, Innate/drug effects , Models, Biological , Pandemics , Pneumonia, Viral/drug therapy , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Safety , Sepsis/drug therapy , Serine Proteinase Inhibitors/adverse effects , Thromboembolism/prevention & control
11.
Basic Clin Pharmacol Toxicol ; 128(2): 204-212, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-919229

ABSTRACT

The coronavirus responsible for COVID-19, SARS-CoV-2, utilizes a viral membrane spike protein for host cell entry. For the virus to engage in host membrane fusion, SARS-CoV-2 utilizes the human transmembrane surface protease, TMPRSS2, to cleave and activate the spike protein. Camostat mesylate, an orally available well-known serine protease inhibitor, is a potent inhibitor of TMPRSS2 and has been hypothesized as a potential antiviral drug against COVID-19. In vitro human cell and animal studies have shown that camostat mesylate inhibits virus-cell membrane fusion and hence viral replication. In mice, camostat mesylate treatment during acute infection with influenza, also dependent on TMPRSS2, leads to a reduced viral load. The decreased viral load may be associated with an improved patient outcome. Because camostat mesylate is administered as an oral drug, it may be used in outpatients as well as inpatients at all disease stages of SARS-CoV-2 infection if it is shown to be an effective antiviral agent. Clinical trials are currently ongoing to test whether this well-known drug could be repurposed and utilized to combat the current pandemic. In the following, we will review current knowledge on camostat mesylate mode of action, potential benefits as an antiviral agent and ongoing clinical trials.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Esters/therapeutic use , Guanidines/therapeutic use , Serine Proteinase Inhibitors/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Drug Repositioning , Esters/administration & dosage , Esters/adverse effects , Guanidines/administration & dosage , Guanidines/adverse effects , Humans , Mice , Patient Safety , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/adverse effects
12.
Front Immunol ; 11: 552925, 2020.
Article in English | MEDLINE | ID: covidwho-843107

ABSTRACT

Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. The clinical manifestations of this disease are pneumonia, lung injury, inflammation, and severe acute respiratory syndrome (SARS). Currently, there is no vaccine or effective pharmacological agents available for the prevention/treatment of SARS-CoV2 infections. Moreover, development of a suitable vaccine is a challenging task due to antibody-dependent enhancement (ADE) and Th-2 immunopathology, which aggravates infection with SARS-CoV-2. Furthermore, the emerging SARS-CoV-2 strain exhibits several distinct genomic and structural patterns compared to other coronavirus strains, making the development of a suitable vaccine even more difficult. Therefore, the identification of novel small molecule inhibitors (NSMIs) that can interfere with viral entry or viral propagation is of special interest and is vital in managing already infected cases. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, the development of novel inhibitors of ACE2/TMPRSS2 is likely to be beneficial in combating SARS-CoV-2 infections. However, the usage of ACE-2 inhibitors to block the SARS-CoV-2 viral entry requires additional studies as there are conflicting findings and severe health complications reported for these inhibitors in patients. Hence, the current interest is shifted toward the development of NSMIs, which includes natural antiviral phytochemicals and Nrf-2 activators to manage a SARS-CoV-2 infection. It is imperative to investigate the efficacy of existing antiviral phytochemicals and Nrf-2 activators to mitigate the SARS-CoV-2-mediated oxidative stress. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections , Drug Delivery Systems , Pandemics , Pneumonia, Viral , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Humans , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , SARS-CoV-2 , Serine Endopeptidases/immunology , Serine Proteinase Inhibitors/therapeutic use , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/immunology , Th2 Cells/immunology , Viral Vaccines/immunology , Viral Vaccines/therapeutic use
13.
Expert Opin Ther Pat ; 30(11): 807-824, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-744458

ABSTRACT

INTRODUCTION: Type II transmembrane serine proteases (TTSPs) of the human respiratory tract generate high interest owing to their ability, among other roles, to cleave surface proteins of respiratory viruses. This step is critical in the viral invasion of coronaviruses, including SARS-CoV-2 responsible for COVID-19, but also influenza viruses and reoviruses. Accordingly, these cell surface enzymes constitute appealing therapeutic targets to develop host-based therapeutics against respiratory viral diseases. Additionally, their deregulated levels or activity has been described in non-viral diseases such as fibrosis, cancer, and osteoarthritis, making them potential targets in these indications. AREAS COVERED: Areas covered: This review includes WIPO-listed patents reporting small molecules and peptide-based inhibitors of type II transmembrane serine proteases of the respiratory tract. EXPERT OPINION: Expert opinion: Several TTSPs of the respiratory tract represent attractive pharmacological targets in the treatment of respiratory infectious diseases (notably COVID-19 and influenza), but also against idiopathic pulmonary fibrosis and lung cancer. The current emphasis is primarily on TMPRSS2, matriptase, and hepsin, yet other TTSPs await validation. Compounds listed herein are predominantly peptidomimetic inhibitors, some with covalent reversible mechanisms of action and high potencies. Their selectivity profile, however, are often only partially characterized. Preclinical data are promising and warrant further advancement in the above diseases.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Patents as Topic , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Respiratory Tract Diseases/drug therapy , Respiratory Tract Diseases/etiology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/therapeutic use , COVID-19 , Humans , Pandemics , Respiratory Tract Diseases/enzymology
15.
Pathog Dis ; 78(7)2020 10 07.
Article in English | MEDLINE | ID: covidwho-733382

ABSTRACT

Influenza virus and coronaviruses continue to cause pandemics across the globe. We now have a greater understanding of their functions. Unfortunately, the number of drugs in our armory to defend us against them is inadequate. This may require us to think about what mechanisms to address. Here, we review the biological properties of these viruses, their genetic evolution and antiviral therapies that can be used or have been attempted. We will describe several classes of drugs such as serine protease inhibitors, heparin, heparan sulfate receptor inhibitors, chelating agents, immunomodulators and many others. We also briefly describe some of the drug repurposing efforts that have taken place in an effort to rapidly identify molecules to treat patients with COVID-19. While we put a heavy emphasis on the past and present efforts, we also provide some thoughts about what we need to do to prepare for respiratory viral threats in the future.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus/drug effects , Drug Repositioning , Influenza, Human/epidemiology , Orthomyxoviridae/drug effects , Pandemics , Anticoagulants/therapeutic use , Antimalarials/therapeutic use , Antioxidants/therapeutic use , Chelating Agents/therapeutic use , Coronavirus/genetics , Coronavirus/growth & development , Coronavirus/pathogenicity , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Glycoconjugates/therapeutic use , Humans , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/virology , Orthomyxoviridae/genetics , Orthomyxoviridae/growth & development , Orthomyxoviridae/pathogenicity , Serine Proteinase Inhibitors/therapeutic use
16.
Cell Mol Biol (Noisy-le-grand) ; 66(3): 221-229, 2020 Jun 05.
Article in English | MEDLINE | ID: covidwho-603065

ABSTRACT

It can be misleading to think that the new severe acute respiratory syndrome coronavirus (SARS-CoV2) which has a very strong mutation and adaptation capabilities, uses only the angiotensin-converting enzyme II (ACE2) pathway to reach target cells. Despite all the precautions taken, the pandemic attack continues and the rapid increase in the number of deaths suggest that this virus has entered the cell through different pathways and caused damage through different mechanisms. The main reason why the ACE2 pathway comes to the fore in all scientific studies is that this receptor is located at the entry point of basic mechanisms that provide alveolo-capillary homeostasis. SARS-CoV-2 has to use nuclear factor-κB (NF-kB), caveloae, clathrin, lipoxin, serine protease and proteasome pathways in addition to ACE2 to enter the target cell and initiate damage. For this reason, while new drug development studies are continuing, in order to be beneficial to patients in their acute period, it is imperative that we are able to come up with drugs that activate or inhibit these pathways and are currently in clinical use. It is also critical that we adopt these new pathways to the treatment of pregnant women affected by SARS-CoV-2, based on the scientific data we use to treat the general population.


Subject(s)
Betacoronavirus/metabolism , Caveolin 1/metabolism , Coronavirus Infections/metabolism , Lipoxins/metabolism , NF-kappa B/metabolism , Pneumonia, Viral/metabolism , Pregnancy Complications, Infectious/metabolism , Proteasome Endopeptidase Complex/metabolism , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2 , Anticholesteremic Agents/therapeutic use , Binding Sites , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/transmission , Coronavirus Infections/virology , Drug Discovery/methods , Drug Repositioning/methods , Female , Humans , Infectious Disease Transmission, Vertical/prevention & control , NF-kappa B/antagonists & inhibitors , Off-Label Use , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Pregnancy , Pregnancy Complications, Infectious/virology , Proteasome Inhibitors/therapeutic use , SARS-CoV-2 , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/therapeutic use , Virus Internalization
17.
Drug Metab Rev ; 52(3): 408-424, 2020 08.
Article in English | MEDLINE | ID: covidwho-602031

ABSTRACT

Despite to outbreaks of highly pathogenic beta and alpha coronaviruses including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and human coronavirus, the newly emerged 2019 coronavirus (COVID-19) is considered as a lethal zoonotic virus due to its deadly respiratory syndrome and high mortality rate among the human. Globally, more than 3,517,345 cases have been confirmed with 243,401 deaths due to Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19. The antiviral drug discovery activity is required to control the persistence of COVID-19 circulation and the potential of the future emergence of coronavirus. However, the present review aims to highlight the important antiviral approaches, including interferons, ribavirin, mycophenolic acids, ritonavir, lopinavir, inhibitors, and monoclonal antibodies (mAbs) to provoke the nonstructural proteins and deactivate the structural and essential host elements of the virus to control and treat the infection of COVID-19 by inhibiting the viral entry, viral RNA replication and suppressing the viral protein expression. Moreover, the present review investigates the epidemiology, diagnosis, structure, and replication of COVID-19 for better understanding. It is recommended that these proteases, inhibitors, and antibodies could be a good therapeutic option in drug discovery to control the newly emerged coronavirus.HighlightsCOVID-19 has more than 79.5% identical sequence to SARS-CoV and a 96% identical sequence of the whole genome of bat coronaviruses.Acute respiratory distress syndrome (ARDS), renal failure, and septic shock are the possible clinical symptoms associated with COVID-19.Different antivirals, including interferons, ribavirin, lopinavir, and monoclonal antibodies (mAbs) could be the potent therapeutic agents against COVID-19.The initial clinical trials on hydroquinone in combination with azithromycin showed an admirable result in the reduction of COVID-19.The overexpression of inflammation response, cytokine dysregulation, and induction of apoptosis could be an well-organized factors to reduce the pathogenicity of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Drug Discovery , Pneumonia, Viral/drug therapy , Antibodies, Monoclonal/therapeutic use , Betacoronavirus/chemistry , Betacoronavirus/genetics , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Humans , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Serine Endopeptidases/physiology , Serine Proteinase Inhibitors/therapeutic use , Virus Replication
18.
J Mol Med (Berl) ; 98(6): 789-803, 2020 06.
Article in English | MEDLINE | ID: covidwho-505727

ABSTRACT

To date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndrome are still unsolved issues causing the severity of this disease. Therefore, immune response modulation and inflammation management can be considered as an essential step. There is no doubt that more studies are required to clarify immunopathogenesis and immune response; however, new therapeutic approaches including mesenchymal stromal cell and immune cell therapy showed inspiring results.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , BCG Vaccine/therapeutic use , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/prevention & control , Coronavirus Infections/therapy , Coronavirus Infections/virology , Humans , Immunization, Passive/methods , Immunotherapy, Adoptive/methods , Janus Kinase Inhibitors/therapeutic use , Mesenchymal Stem Cell Transplantation/methods , Nanomedicine/methods , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , SARS-CoV-2 , Serine Proteinase Inhibitors/therapeutic use
19.
Molecules ; 25(10)2020 05 22.
Article in English | MEDLINE | ID: covidwho-343433

ABSTRACT

Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2') cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2' cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Serine Proteases/metabolism , Serine Proteinase Inhibitors/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Animals , Antigens, Bacterial/toxicity , Antiviral Agents/therapeutic use , Bacterial Toxins/toxicity , Betacoronavirus/pathogenicity , Binding Sites , COVID-19 , Drug Delivery Systems , Female , Furin/pharmacology , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Pandemics , RAW 264.7 Cells , SARS-CoV-2 , Serine Proteinase Inhibitors/therapeutic use , Spike Glycoprotein, Coronavirus/chemistry
20.
Exp Biol Med (Maywood) ; 245(11): 964-969, 2020 06.
Article in English | MEDLINE | ID: covidwho-72254

ABSTRACT

IMPACT STATEMENT: Early availability of the sequence, the genetic material of SARS-CoV-2 (the virus that causes COVID-19), has prompted efforts towards identifying a safe and effective vaccine in the current public health emergency. To that end, understanding the pathophysiology of disease is crucial for scientists around the world. Since conventional vaccine development and manufacturing may take several years, it is important to think about alternative strategies that we could use to mitigate imminent catastrophe. We hope that this article will open up new avenues and provide insights that could potentially save hundreds of lives affected by COVID-19.


Subject(s)
Betacoronavirus/genetics , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , China/epidemiology , Communicable Disease Control/methods , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Genome, Viral/genetics , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , SARS Virus/genetics , SARS-CoV-2 , Serine Proteinase Inhibitors/therapeutic use
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