Selected article for: "acute respiratory syndrome and additional combination"
Author: Bakowski, Malina A.; Beutler, Nathan; Wolff, Karen C.; Kirkpatrick, Melanie G.; Chen, Emily; Nguyen, Tu-Trinh H.; Riva, Laura; Shaabani, Namir; Parren, Mara; Ricketts, James; Gupta, Anil K.; Pan, Kastin; Kuo, Peiting; Fuller, MacKenzie; Garcia, Elijah; Teijaro, John R.; Yang, Linlin; Sahoo, Debashis; Chi, Victor; Huang, Edward; Vargas, Natalia; Roberts, Amanda J.; Das, Soumita; Ghosh, Pradipta; Woods, Ashley K.; Joseph, Sean B.; Hull, Mitchell V.; Schultz, Peter G.; Burton, Dennis R.; Chatterjee, Arnab K.; McNamara, Case W.; Rogers, Thomas F.
Title: Drug repurposing screens identify chemical entities for the development of COVID-19 interventions
  • Cord-id: 5qk8adrn
  • Document date: 2021_6_3
    • ID: 5qk8adrn
    Snippet: 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
    Document: 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.

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