Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

Abstract

Coronavirus disease 19 (COVID-19) is a severe acute respiratory syndrome caused by SARS-CoV-2 (2019-nCoV). While no drugs have yet been approved to treat this disease, small molecules effective against other viral infections are under clinical evaluation for therapeutic abatement of SARS-CoV-2 infections. Ongoing clinical trials include Kaletra (a combination of two protease inhibitors approved for HIV treatment), remdesivir (an investigational drug targeting RNA-dependent RNA polymerase [RdRP] of SARS-CoV-2), and hydroxychloroquine (an approved anti-malarial and immuno-modulatory drug). Since SARS-CoV-2 replication depends on three virally encoded proteins (RdRP, papain-like proteinase, and helicase), we screened 54 FDA-approved antiviral drugs and ~3300 investigational drugs for binding to these proteins using targeted and unbiased docking simulations and computational modeling. Elbasvir, a drug approved for treating hepatitis C, is predicted to bind stably and preferentially to all three proteins. At the therapeutic dosage, elbasvir has low toxicity (liver enzymes transiently elevated in 1% of subjects) and well-characterized drug-drug interactions. We predict that treatment with elbasvir, alone or in combination with other drugs such as grazoprevir, could efficiently block SARS-CoV-2 replication. The concerted action of elbasvir on at least three targets essential for viral replication renders viral mutation to drug resistance extremely unlikely.

Molecular mechanisms of the novel coronavirus SARS-CoV-2 and potential anti-COVID19 pharmacological targets since the outbreak of the pandemic

“…Vapreotide, an AIDS-related diarrhea drug, was found to exhibit the lowest binding free energy amongst 23 approved antivirals in a computer-aided drug design pipeline ( Borgio et al, 2020 ). Similar approaches have identified cmp1, cmp3a, cmp11 and cmp15 to competitively bind at the NTP binding site ( Mirza and Froeyen, 2020 ), and elbasvir, approved for HCV treatment, to inhibit not only helicase activity by blocking ssDNA binding, but also RNA binding to RdRP ( Balasubramaniam and Reis, 2020 ).…”

Antivirals Against Coronaviruses: Candidate Drugs for SARS-CoV-2 Treatment?

“…By narrowing down the number of drug candidates, in silico studies have the potential to avoid the laborious and generally costly synthesis of many of these compounds (Lengauer and Sing, 2006;Villegas-Rosales et al, 2012). Nevertheless, several predicted compounds in the literature have only been screened by in silico and/or interaction assays (Chen et al, 2005;Kaeppler et al, 2005;Lee et al, 2005;Kim et al, 2012;Arya et al, 2020;Balasubramaniam and Reis, 2020), which ultimately hinders the proper assessment of the antiviral activities of the compounds. Therefore, it is imperative that these studies be associated with in vitro and in vivo assays in order to confirm the predicted activities in biological models and also to evaluate pharmacological outcomes (National Research Council (US) Committee on Applications of Toxicogenomic Technologies to Predictive Toxicology, 2007).…”

Simultaneous Inhibition of Entry and Replication of Novel Corona Virus by Grazoprevir: A Computational Drug Repurposing Study

“…As predicted, grazoprevir interacts with all three proteins (host cell as well as virion) optimally with stable binding conformations. Since, this drug, grazoprevir, is marketed as fixed-dose combinations with elbasvir (Zepatier TM ), which was also reported to have anti-COVID activity recently 23 . Thus, it is encouraging for effective drug combinations to derive their synergistic effects.…”