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Clinical Antiviral Drug Arbidol Inhibits Infection by SARS-CoV-2 and Variants through Direct Binding to the Spike Protein.

ABSTRACT: Arbidol (ARB) is a broad-spectrum antiviral drug approved in Russia and China for the treatment of influenza. ARB was tested in patients as a drug candidate for the treatment at the early onset of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite promising clinical results and multiple ongoing trials, preclinical data are lacking and the molecular mechanism of action of ARB against SARS-CoV-2 remains unknown. Here, we demonstrate that ARB binds to the spike viral fusion glycoprotein of the SARS-CoV-2 Wuhan strain as well as its more virulent variants from the United Kingdom (strain B.1.1.7) and South Africa (strain B.1.351). We pinpoint the ARB binding site on the S protein to the S2 membrane fusion domain and use an infection assay with Moloney murine leukemia virus (MLV) pseudoviruses (PVs) pseudotyped with the S proteins of the Wuhan strain and the new variants to show that this interaction is sufficient for the viral cell entry inhibition by ARB. Finally, our experiments reveal that the ARB interaction leads to a significant destabilization and eventual lysosomal degradation of the S protein in cells. Collectively, our results identify ARB as the first clinically approved small molecule drug binder of the SARS-CoV-2 S protein and place ARB among the more promising drug candidates for COVID-19.

SUBMITTER: Shuster A

PROVIDER: S-EPMC8610013 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The Antiviral Drug Arbidol Inhibits Zika Virus.

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Project description: Not available

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Targeting the receptor binding domain and heparan sulfate binding for antiviral drug development against SARS-CoV-2 variants.

Project description:The emergence of SARS-CoV-2 variants diminished the efficacy of current antiviral drugs and vaccines. Hence, identifying highly conserved sequences and potentially druggable pockets for drug development was a promising strategy against SARS-CoV-2 variants. In viral infection, the receptor-binding domain (RBD) proteins are essential in binding to the host receptor. Others, Heparan sulfate (HS), widely distributed on the surface of host cells, is thought to play a central role in the viral infection cycle of SARS-CoV-2. Therefore, it might be a reasonable strategy for antiviral drug design to interfere with the RBD in the HS binding site. In this study, we used computational approaches to analyze multiple sequences of coronaviruses and reveal important information about the binding of HS to RBD in the SARS-CoV-2 spike protein. Our results showed that the potential hot-spots, including R454 and E471, in RBD, exhibited strong interactions in the HS-RBD binding region. Therefore, we screened different compounds in the natural product database towards these hot-spots to find potential antiviral candidates using LibDock, Autodock vina and furthermore applying the MD simulation in AMBER20. The results showed three potential natural compounds, including Acetoside (ACE), Hyperoside (HYP), and Isoquercitrin (ISO), had a strong affinity to the RBD. Our results demonstrate a feasible approach to identify potential antiviral agents by evaluating the binding interaction between viral glycoproteins and host receptors. The present study provided the applications of the structure-based computational approach for designing and developing of new antiviral drugs against SARS-CoV-2 variants.

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