DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

Jimmidi, Ravikumar; Chamakuri, Srinivas; Lu, Shuo; Ucisik, Melek Nihan; Chen, Peng-Jen; Bohren, Kurt M.; Moghadasi, Seyed Arad; Versteeg, Leroy; Nnabuife, Christina; Li, Jian-Yuan; Qin, Xuan; Chen, Ying-Chu; Faver, John C.; Nyshadham, Pranavanand; Sharma, Kiran L.; Sankaran, Banumathi; Judge, Allison; Yu, Zhifeng; Li, Feng; Pollet, Jeroen; Harris, Reuben S.; Matzuk, Martin M.; Palzkill, Timothy; Young, Damian W.

doi:10.1038/s42004-023-00961-y

Title: DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

Journal Article · 03 August 2023 · Communications Chemistry

DOI: https://doi.org/10.1038/s42004-023-00961-y · OSTI ID:2228857

Jimmidi, Ravikumar ^[1];

^[1]; Lu, Shuo ^[1]; Ucisik, Melek Nihan ^[1]; Chen, Peng-Jen ^[1];

^[1]; Moghadasi, Seyed Arad ^[2]; Versteeg, Leroy ^[3];

^[1]; Li, Jian-Yuan ^[1];

^[1]; Chen, Ying-Chu ^[1]; Faver, John C. ^[1]; Nyshadham, Pranavanand ^[1]; Sharma, Kiran L. ^[1];

^[4];

^[1]; Yu, Zhifeng ^[1];

^[1];

^[3] more »

Baylor College of Medicine, Houston, TX (United States)
Univ. of Minnesota, Minneapolis, MN (United States)
Baylor College of Medicine, Houston, TX (United States); Texas Children’s Hospital, Houston, TX (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
University of Texas Health Science Center, San Antonio, TX (United States)

The development of SARS-CoV-2 main protease (M^pro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M^pro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M^pro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M^pro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M^pro with low nanomolar K_i values. Furthermore, these compounds demonstrate efficacy against mutant forms of M^pro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2228857

Journal Information:: Communications Chemistry, Journal Name: Communications Chemistry Journal Issue: 1 Vol. 6; ISSN 2399-3669

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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Title: DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

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