The FDA-approved drug cobicistat synergizes with remdesivir to inhibit SARS-CoV-2 replication

Abstract

Combinations of direct-acting antivirals are needed to minimize drug-resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) and testing of a number of drug regimens has led to conflicting results. Here we show that cobicistat, which is an-FDA approved drug-booster that blocks the activity of the drug metabolizing proteins Cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Cell-to-cell membrane fusion assays indicated that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with the putative CYP3A target and nucleoside analog remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. The cobicistat/remdesivir combination was able to potently abate viral replication to levels comparable to mock-infected cells leading to an almost complete rescue of infected cell viability. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19.

COVID-19: A Review of Potential Treatments (Corticosteroids, Remdesivir, Tocilizumab, Bamlanivimab/Etesevimab, and Casirivimab/Imdevimab) and Pharmacological Considerations

“…A synergistic effect on suppression of SARS-CoV-2 replication in vitro has been suggested between cobicistat and RDV, but the clinical relevance of this is unclear. 31 Tocilizumab COVID-19 patients may experience a cytokine storm or cytokine release syndrome (CRS), which is an overreaction of the immune system, characterized by the release of IL-6, IL-1, IL-2, IL-8, TNFα, and other inflammatory mediators. 32 Excessive cytokine release activates immune cells to release free radicals, resulting in ARDS, multiorgan failures, and potentially death.…”

“…A synergistic effect on suppression of SARS-CoV-2 replication in vitro has been suggested between cobicistat and RDV, but the clinical relevance of this is unclear. 31…”

An updated review on potential therapeutic drug candidates, vaccines and an insight on patents filed for COVID-19

“…As on date there are 41 ongoing clinical trials to check the efficacy of remdesivir against COVID-19. CYP3A inhibitors are potential boosters of other antivirals as well, in particular remdesivir (Shytaj et al, 2021;Xie and Wang, 2021).…”

Combinations of drugs might increase the survival chances of COVID-19 patients: Literature review till date

“…Remdesivir and Ledipasvir among the FDA-Approved Antiviral Drugs Have Potential to Inhibit SARS-CoV-2 Replication [47]. A prepint by Iart et.al reported that cobicistat synergizes with Remdesivir to inhibit SARS-CoV-2 replication [48].…”