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DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors
- Source :
- Communications Chemistry, Vol 6, Iss 1, Pp 1-10 (2023)
- Publication Year :
- 2023
- Publisher :
- Nature Portfolio, 2023.
-
Abstract
- 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 K i 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.
Details
- Language :
- English
- ISSN :
- 23993669
- Volume :
- 6
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Communications Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.b44f4c21884a5ab19d7b954a87359d
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s42004-023-00961-y