1. DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.
- Author
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Jimmidi R, Chamakuri S, Lu S, Ucisik MN, Chen PJ, Bohren KM, Moghadasi SA, Versteeg L, Nnabuife C, Li JY, Qin X, Chen YC, Faver JC, Nyshadham P, Sharma KL, Sankaran B, Judge A, Yu Z, Li F, Pollet J, Harris RS, Matzuk MM, Palzkill T, and Young DW
- Abstract
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 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., (© 2023. Springer Nature Limited.)- Published
- 2023
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