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 H Nguyen, Laura Riva, Namir Shaabani, Mara Parren, James Ricketts, Anil K Gupta, Kastin 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 V Hull, Peter G Schultz, Dennis R Burton, Arnab K Chatterjee, Case W McNamara, Thomas F Rogers
Author Information
Malina A Bakowski: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA. mbakowski@scripps.edu. ORCID
Nathan Beutler: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. ORCID
Karen C Wolff: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Melanie G Kirkpatrick: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Emily Chen: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Tu-Trinh H Nguyen: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Laura Riva: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Namir Shaabani: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. ORCID
Mara Parren: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
James Ricketts: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. ORCID
Anil K Gupta: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Kastin Pan: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Peiting Kuo: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA. ORCID
MacKenzie Fuller: Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA.
Elijah Garcia: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
John R Teijaro: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
Linlin Yang: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
Debashis Sahoo: Department of Computer Science and Engineering, Jacobs School of Engineering, UC San Diego, La Jolla, CA, USA. ORCID
Victor Chi: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Edward Huang: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Natalia Vargas: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA. ORCID
Amanda J Roberts: Animal Models Core Facility, The Scripps Research Institute, La Jolla, CA, USA.
Soumita Das: HUMANOID CoRE, UC San Diego, La Jolla, CA, USA. ORCID
Pradipta Ghosh: Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, USA. ORCID
Ashley K Woods: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Sean B Joseph: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA. ORCID
Mitchell V Hull: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Peter G Schultz: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Dennis R Burton: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. ORCID
Arnab K Chatterjee: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA.
Case W McNamara: Calibr, a division of The Scripps Research Institute, La Jolla, CA, USA. ORCID
Thomas F Rogers: Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. trogers@scripps.edu. ORCID
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.
