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

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.