During the replication process of SARS-CoV-2, the main protease of the virus [3-chymotrypsin-like protease (3CL^pro)] plays a pivotal role and is essential for the life cycle of the pathogen. Numerous studies have been conducted so far, which have confirmed 3CL^pro as an attractive drug target to combat COVID-19. We describe a novel and efficient next-generation sequencing (NGS) supported phage display selection strategy for the identification of a set of SARS-CoV-2 3CL^pro targeting peptide ligands that inhibit the 3CL protease, in a competitive or noncompetitive mode, in the low μM range. From the most efficient l-peptides obtained from the phage display, we designed all-d-peptides based on the retro-inverso (ri) principle.

https://doi.org/10.1021/acschembio.2c00735