DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

Conventional structure-based design of M-pro inhibitors of SARS-CoV-2 often starts from the structural information of M-pro and their binders; however, the continual rise of resistant strains requires innovative routes to discover new inhibitors. Here, the authors develop a DNA-encoded chemical library screening to produce non-covalent, non-peptidic small molecule inhibitors for SARS-CoV-2 M-pro independently of preliminary knowledge regarding suitable starting points. 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 M-pro 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 M-pro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M-pro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M-pro with low nanomolar K-i values. Furthermore, these compounds demonstrate efficacy against mutant forms of M-pro 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.