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Drug repurposing screens identify chemical entities for the development of COVID-19 interventions.

ABSTRACT: The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here, we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. We screen a best-in-class drug repurposing library, ReFRAME, against two high-throughput, high-content imaging infection assays: one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells. From nearly 12,000 compounds, we identify 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting SARS-CoV-2 replication. Notably, most screen hits are cell-line specific, likely due to different virus entry mechanisms or host cell-specific sensitivities to modulators. Among these promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 possess desirable in vitro activity, pharmacokinetic and human safety profiles, and both reduce SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. Furthermore, MK-4482 effectively blocks SARS-CoV-2 infection in a hamster model. Overall, we identify direct-acting antivirals as the most promising compounds for drug repurposing, additional compounds that may have value in combination therapies, and tool compounds for identification of viral host cell targets.

SUBMITTER: Bakowski MA

PROVIDER: S-EPMC8175350 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Exhaustive drug repurposing strategies support the pursuit of new chemical entities for the development of effective COVID-19 interventions

Project description:The ongoing pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), necessitates strategies to identify prophylactic and therapeutic drug candidates for rapid clinical deployment. Here we describe a screening pipeline for the discovery of efficacious SARS-CoV-2 inhibitors. Two high-throughput, high-content imaging infection assays (one using HeLa cells expressing SARS-CoV-2 receptor ACE2 and the other using lung epithelial Calu-3 cells) were developed and used to screen ReFRAME, a best-in-class drug repurposing library. Among the promising hits, the antivirals nelfinavir and the parent of prodrug MK-4482 had most favorable in vitro activity, pharmacokinetic and human safety profiles, and both reduced SARS-CoV-2 replication in an orthogonal human differentiated primary cell model. However, only MK-4482 effectively blocked SARS-CoV-2 infection in a hamster model, likely due to inadequate plasma exposure of nelfinavir.

2021-04-02 | GSE168095 | GEO

Exhaustive drug repurposing strategies support the pursuit of new chemical entities for the development of effective COVID-19 interventions

Project description:Exhaustive drug repurposing strategies support the pursuit of new chemical entities for the development of effective COVID-19 interventions

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