Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

Abstract

<jats:title>Abstract</jats:title> <jats:p>Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted <jats:italic>in vitro</jats:italic>, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (M<jats:sup>pro</jats:sup>) in cell culture and <jats:italic>in vitro</jats:italic> enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC<jats:sub>50</jats:sub> of 13.7 µM. Atazanavir on the other hand was the only PI to inhibit the viral protease both in cell culture and in our <jats:italic>in vitro</jats:italic> enzymatic assay. Conclusion Targeting of SARS-CoV-2 M<jats:sup>pro</jats:sup> by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 M<jats:sup>pro</jats:sup>.</jats:p>

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“…However, 11r was not identified as a strong binder with c36. From the experimental data 25,62 , the binding free energies of 11r, 13a, 13b, darunavir ligands were -9.23, -7.70, -8.45, and -6.14 kcal/mol, respectively. In terms of consistency with experimental data, MM-PBSA with ffSB99 correctly identified 11r as the strongest binder.…”

In silico Analyses of Immune System Protein Interactome Network, Single-Cell RNA Sequencing of Human Tissues, and Artificial Neural Networks Reveal Potential Therapeutic Targets for Drug Repurposing Against COVID-19

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