2-Substituted oxazolyl and thiazolyl amino acids are suitable P1 surrogates for new SARS-CoV-2 main protease inhibitors

Abstract

The SARS-CoV-2 main protease is a cysteine protease that can bind in a reversible covalent fashion to the warhead of peptidic inhibitors. The most commonly used P1 amino acid subunit in SARS-CoV-2 therapeutics is a cyclic glutamine derivative, and this moiety has been shown to be relatively quickly metabolized, but contains heteroatoms that interact with key residues in the active site. Here, a structure–activity study has been explored with the synthesis of oxazolyl and thiazolyl unnatural amino acids as P1 moieties. This investigation involved different substitution patterns of these heteroaromatic rings, in an effort to maintain a scaffold that can form the important interactions with residues in the active site. IC₅₀ values with the SARS-CoV-2 main protease reveal the 2-oxazolyl and 2-thiazolyl derivatives are similarly effective (290 nM and 270 nM, respectively) to compounds with the cyclic glutamine derivative, demonstrating alternative P1 moieties that can be used in the efficient design of novel coronavirus main protease inhibitors.