Ravikumar Jimmidi; Srinivas Chamakuri; Shuo Lu; Melek Nihan Ucisik; Peng-Jen Chen; Kurt M. Bohren; Seyed Arad Moghadasi; Leroy Versteeg; Christina Nnabuife; Jian-Yuan Li; Xuan Qin; Ying-Chu Chen; John C. Faver; Pranavanand Nyshadham; Kiran L. Sharma; Banumathi Sankaran; Allison Judge; Zhifeng Yu; Feng Li; Jeroen Pollet; Reuben S. Harris; Martin M. Matzuk; Timothy Palzkill; Damian W. Young
Commun. Chem., 2023, 6, 164
https://doi.org/10.1038/s42004-023-00961-y

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.