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 and Thomas F. Rogers ()
Additional contact information
Malina A. Bakowski: Calibr, a division of The Scripps Research Institute
Nathan Beutler: The Scripps Research Institute
Karen C. Wolff: Calibr, a division of The Scripps Research Institute
Melanie G. Kirkpatrick: Calibr, a division of The Scripps Research Institute
Emily Chen: Calibr, a division of The Scripps Research Institute
Tu-Trinh H. Nguyen: Calibr, a division of The Scripps Research Institute
Laura Riva: Calibr, a division of The Scripps Research Institute
Namir Shaabani: The Scripps Research Institute
Mara Parren: The Scripps Research Institute
James Ricketts: The Scripps Research Institute
Anil K. Gupta: Calibr, a division of The Scripps Research Institute
Kastin Pan: Calibr, a division of The Scripps Research Institute
Peiting Kuo: Calibr, a division of The Scripps Research Institute
MacKenzie Fuller: UC San Diego
Elijah Garcia: The Scripps Research Institute
John R. Teijaro: The Scripps Research Institute
Linlin Yang: The Scripps Research Institute
Debashis Sahoo: Jacobs School of Engineering, UC San Diego
Victor Chi: Calibr, a division of The Scripps Research Institute
Edward Huang: Calibr, a division of The Scripps Research Institute
Natalia Vargas: Calibr, a division of The Scripps Research Institute
Amanda J. Roberts: The Scripps Research Institute
Soumita Das: HUMANOID CoRE, UC San Diego
Pradipta Ghosh: UC San Diego
Ashley K. Woods: Calibr, a division of The Scripps Research Institute
Sean B. Joseph: Calibr, a division of The Scripps Research Institute
Mitchell V. Hull: Calibr, a division of The Scripps Research Institute
Peter G. Schultz: Calibr, a division of The Scripps Research Institute
Dennis R. Burton: The Scripps Research Institute
Arnab K. Chatterjee: Calibr, a division of The Scripps Research Institute
Case W. McNamara: Calibr, a division of The Scripps Research Institute
Thomas F. Rogers: The Scripps Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-23328-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23328-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-23328-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().