The anti‐HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV‐2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID‐19 infections

Autor: Farhana Musarrat, Vladimir N. Chouljenko, Konstantin G. Kousoulas, Tamara Chouljenko, Achyut Dahal, Seetharama D. Jois, Rafiq Nabi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
viruses
coronavirus
medicine.disease_cause
Giant Cells
Membrane Fusion
Cell Fusion
0302 clinical medicine
Chlorocebus aethiops
HIV Protease Inhibitor
entry inhibitors
030212 general & internal medicine
virus classification
Research Articles
glycoproteins
Coronavirus
Cell fusion
Nelfinavir
Chemistry
virus diseases
Recombinant Proteins
Molecular Docking Simulation
Infectious Diseases
Severe acute respiratory syndrome-related coronavirus
Spike Glycoprotein
Coronavirus
030211 gastroenterology & hepatology
medicine.drug
Plasmids
Protein Binding
Research Article
SARS coronavirus
Anti-HIV Agents
Virus
03 medical and health sciences
Viral envelope
Virology
antiviral agents
medicine
fusion protein
Animals
Humans
Protein Interaction Domains and Motifs
Vero Cells
Binding Sites
SARS-CoV-2
Virion
biochemical phenomena
metabolism
and nutrition
infection
COVID-19 Drug Treatment
Vero cell
cellular effect
Nelfinavir mesylate
Zdroj: Journal of Medical Virology
ISSN: 1096-9071
0146-6615
DOI: 10.1002/jmv.25985
Popis: Severe acute respiratory syndrome coronavirus‐2 (SARS CoV‐2) is the causative agent of the coronavirus disease‐2019 (COVID‐19) pandemic. Coronaviruses enter cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after virion endocytosis. The spike (S) glycoprotein is a major determinant of virus infectivity. Herein, we show that the transient expression of the SARS CoV‐2 S glycoprotein in Vero cells caused extensive cell fusion (formation of syncytia) in comparison to limited cell fusion caused by the SARS S glycoprotein. Both S glycoproteins were detected intracellularly and on transfected Vero cell surfaces. These results are in agreement with published pathology observations of extensive syncytia formation in lung tissues of patients with COVID‐19. These results suggest that SARS CoV‐2 is able to spread from cell‐to‐cell much more efficiently than SARS effectively avoiding extracellular neutralizing antibodies. A systematic screening of several drugs including cardiac glycosides and kinase inhibitors and inhibitors of human immunodeficiency virus (HIV) entry revealed that only the FDA‐approved HIV protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S‐n‐ and S‐o‐mediated cell fusion with complete inhibition at a 10‐μM concentration. In‐silico docking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S‐n‐ and S‐o‐mediated membrane fusion. Also, it is possible that nelfinavir may act to inhibit S proteolytic processing within cells. These results warrant further investigations of the potential of nelfinavir mesylate to inhibit virus spread at early times after SARS CoV‐2 symptoms appear.
Highlights Nelfinavir (Viracept) Inhibits SARS CoV‐2 Spike‐mediated cell fusionSARS CoV‐2 Spike glycoprotein is highly fusogenic in comparison to SARS CoV Spike glycoproteinCell fusion and extensive syncytia formation is projected to be an important determinant of SARS CoV infectivity, spread and pathogenicity
Databáze: OpenAIRE
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