GSE168095
Exhaustive drug repurposing strategies support the pursuit of new chemical entities for the development of effective COVID-19 interventions
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. Overall design: Hamster lung from uninfected (U, n=2), vehicle treated (V, n=4) and MK-4482 (EIDD-2801) treated (T, n=4) samples were analyzed using RNASeq platform.