1. DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors
- Author
-
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, and Young, Damian W
- Subjects
Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biodefense ,Vaccine Related ,Infectious Diseases ,Prevention ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Chemical sciences - 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.
- Published
- 2023