Language
English
Publication Date
8-4-2023
Journal
Communications Chemistry
DOI
10.1038/s42004-023-00961-y
PMID
37542196
PMCID
PMC10403511
PubMedCentral® Posted Date
8-4-2023
PubMedCentral® Full Text Version
Post-print
Abstract
The development of SARS-CoV-2 main protease (Mpro) 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 Mpro 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 Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro 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.
Keywords
Drug discovery and development, Drug discovery and development, Chemical libraries, Screening
Published Open-Access
yes
Recommended Citation
Jimmidi, Ravikumar; Chamakuri, Srinivas; Lu, Shuo; et al., "DNA-Encoded Chemical Libraries Yield Non-covalent and Non-peptidic SARS-CoV-2 Main Protease Inhibitors" (2023). Faculty and Staff Publications. 387.
https://digitalcommons.library.tmc.edu/baylor_docs/387
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Clinical Epidemiology Commons, COVID-19 Commons, Medical Cell Biology Commons, Medical Specialties Commons