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Molecules ; 25(16)2020 Aug 17.
Article in English | MEDLINE | ID: covidwho-717752


A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been the cause of a recent global pandemic. The highly contagious nature of this life-threatening virus makes it imperative to find therapies to counteract its diffusion. The main protease (Mpro) of SARS-CoV-2 is a promising drug target due to its indispensable role in viral replication inside the host. Using a combined two-steps approach of virtual screening and molecular docking techniques, we have screened an in-house collection of small molecules, mainly composed of natural and nature-inspired compounds. The molecules were selected with high structural diversity to cover a wide range of chemical space into the enzyme pockets. Virtual screening experiments were performed using the blind docking mode of the AutoDock Vina software. Virtual screening allowed the selection of structurally heterogeneous compounds capable of interacting effectively with the enzymatic site of SARS-CoV-2 Mpro. The compounds showing the best interaction with the protein were re-scored by molecular docking as implemented in AutoDock, while the stability of the complexes was tested by molecular dynamics. The most promising candidates revealed a good ability to fit into the protein binding pocket and to reach the catalytic dyad. There is a high probability that at least one of the selected scaffolds could be promising for further research.

Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Biological Products/pharmacology , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Protease Inhibitors/pharmacology , Drug Repositioning , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptide Hydrolases/metabolism , Viral Matrix Proteins/antagonists & inhibitors
Cardiovasc Res ; 116(10): 1733-1741, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-637912


AIMS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly binds to ACE2 (angiotensin-converting enzyme 2) to facilitate cellular entry. Compared with the lung or respiratory tract, the human heart exhibits greater ACE2 expression. However, little substantial damage was found in the heart tissue, and no viral particles were observed in the cardiac myocytes. This study aims to analyse ACE2 and SARS-CoV-2 spike (S) protein proteases at the single-cell level, to explore the cardiac involvement in COVID-19 and improve our understanding of the potential cardiovascular implications of COVID-19. METHODS AND RESULTS: With meta-analysis, the prevalence of cardiac injury in COVID-19 patients varies from 2% [95% confidence interval (CI) 0-5%, I2 = 0%] in non-ICU patients to 59% (95% CI 48-71%, I2 = 85%) in non-survivors. With public single-cell sequence data analysis, ACE2 expression in the adult human heart is higher than that in the lung (adjusted P < 0.0001). Inversely, the most important S protein cleavage protease TMPRSS2 (transmembrane protease serine protease-2) in the heart exhibits an extremely lower expression than that in the lung (adjusted P < 0.0001), which may restrict entry of SARS-CoV-2 into cardiac cells. Furthermore, we discovered that other S protein proteases, CTSL (cathepsin L) and FURIN (furin, paired basic amino acid cleaving enzyme), were expressed in the adult heart at a similar level to that in the lung, which may compensate for TMPRSS2, mediating cardiac involvement in COVID-19. CONCLUSION: Compared with the lung, ACE2 is relatively more highly expressed in the human heart, while the key S protein priming protease, TMPRSS2, is rarely expressed. The low percentage of ACE2+/TMPRSS2+ cells reduced heart vulnerability to SARS-CoV-2 to some degree. CTSL and FURIN may compensate for S protein priming to mediate SARS-CoV-2 infection of the heart.

Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Myocardium/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Single-Cell Analysis , Spike Glycoprotein, Coronavirus/metabolism , Humans , Lung/metabolism , Lung/virology , Pandemics , Peptide Hydrolases/metabolism , Proteolysis
Elife ; 92020 05 26.
Article in English | MEDLINE | ID: covidwho-378182


Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 66 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.

Betacoronavirus/metabolism , Coronavirus Infections/virology , Epithelial Sodium Channels/metabolism , Molecular Mimicry , Peptide Hydrolases/metabolism , Pneumonia, Viral/virology , Viral Envelope Proteins/metabolism , Viral Proteins/metabolism , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Epithelial Sodium Channels/genetics , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Proteolysis , Substrate Specificity , Viral Envelope Proteins/genetics , Viral Proteins/genetics