Drug repurposing screens identify chemical entities for the development of COVID-19 interventions
Malina A. Bakowski, Nathan Beutler, Karen C. Wolff, Melanie G. Kirkpatrick, Emily Chen, Tu-Trinh Nguyen, Laura Riva, Namir Shaabani, Mara Parren, James Ricketts, Anil Kumar Gupta, K. Pan, Peiting Kuo, Mackenzie Fuller, Elijah Garcia, John R. Teijaro, Linlin Yang, Debashis Sahoo, Victor Chi, Edward Huang, Natalia Vargas, Amanda J. Roberts, Soumita Das, Pradipta Ghosh, Ashley K. Woods, Sean B. Joseph, Mitchell Hull, Peter G. Schultz, Dennis R. Burton, Arnab K. Chatterjee, Case W. McNamara, Thomas F. Rogers
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.