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Molecules ; 26(16)2021 Aug 12.
Article in English | MEDLINE | ID: covidwho-1355016


The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys11, Lys12,Lys13-(pBthTX-I)2K ((pBthTX-I)2K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)2K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC50 = 28-65 µM) and mostly low cytotoxic effect (CC50 > 100 µM). To shed light on the mechanism of action underlying the peptides' antiviral activity, the Main Protease (Mpro) and Papain-Like protease (PLpro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PLpro inhibition potencies (IC50s = 1.0-3.5 µM) and binding affinities (Kd = 0.9-7 µM) at the low micromolar range but poor inhibitory activity against Mpro (IC50 > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PLpro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.

Crotalid Venoms/chemistry , Dimerization , Papain/antagonists & inhibitors , Peptides/chemistry , Peptides/pharmacology , SARS-CoV-2/enzymology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Molecular Docking Simulation , Papain/chemistry , Papain/metabolism , Peptides/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Protein Conformation , SARS-CoV-2/drug effects
J Chem Phys ; 153(11): 115101, 2020 Sep 21.
Article in English | MEDLINE | ID: covidwho-796705


Broad-spectrum antiviral drugs are urgently needed to stop the Coronavirus Disease 2019 pandemic and prevent future ones. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is related to the SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which have caused the previous outbreaks. The papain-like protease (PLpro) is an attractive drug target due to its essential roles in the viral life cycle. As a cysteine protease, PLpro is rich in cysteines and histidines, and their protonation/deprotonation modulates catalysis and conformational plasticity. Here, we report the pKa calculations and assessment of the proton-coupled conformational dynamics of SARS-CoV-2 in comparison to SARS-CoV and MERS-CoV PLpros using the recently developed graphical processing unit (GPU)-accelerated implicit-solvent continuous constant pH molecular dynamics method with a new asynchronous replica-exchange scheme, which allows computation on a single GPU card. The calculated pKa's support the catalytic roles of the Cys-His-Asp triad. We also found that several residues can switch protonation states at physiological pH among which is C270/271 located on the flexible blocking loop 2 (BL2) of SARS-CoV-2/CoV PLpro. Simulations revealed that the BL2 can open and close depending on the protonation state of C271/270, consistent with the most recent crystal structure evidence. Interestingly, despite the lack of an analogous cysteine, BL2 in MERS-CoV PLpro is also very flexible, challenging a current hypothesis. These findings are supported by the all-atom fixed-charge simulations and provide a starting point for more detailed studies to assist the structure-based design of broad-spectrum inhibitors against CoV PLpros.

Antiviral Agents/pharmacology , Betacoronavirus/enzymology , Drug Design , Middle East Respiratory Syndrome Coronavirus/enzymology , Molecular Dynamics Simulation , Papain/chemistry , Papain/metabolism , Protons , Amino Acid Sequence , Histidine , Hydrogen-Ion Concentration , Papain/antagonists & inhibitors , Protein Domains , SARS-CoV-2
Bioessays ; 42(11): e2000094, 2020 11.
Article in English | MEDLINE | ID: covidwho-723430


More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here

Adrenergic beta-Antagonists/pharmacology , Adrenergic beta-Antagonists/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/physiology , COVID-19 , Carvedilol/pharmacology , Carvedilol/therapeutic use , Coronavirus Infections/epidemiology , Coronavirus Papain-Like Proteases , Drug Repositioning/methods , Humans , Inflammasomes/drug effects , Inflammasomes/metabolism , Inflammation Mediators/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pandemics , Papain/antagonists & inhibitors , Papain/metabolism , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Pulmonary Embolism/prevention & control , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Respiratory Insufficiency/prevention & control , SARS-CoV-2 , Shock, Septic/prevention & control , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Virus Internalization/drug effects