The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery.

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M^pro) autocatalytically releases itself out of the viral polyprotein to form a fully active mature dimer in a manner that is not fully understood. Here, we introduce several tools to help elucidate differences between cis (intramolecular) and trans (intermolecular) proteolytic processing and to evaluate inhibition of precursor M^pro. We found that many mutations at the P1 position of the N-terminal autoprocessing site do not block cis autoprocessing but do inhibit trans processing. Notably, substituting the WT glutamine at the P1 position with isoleucine retains M^pro in an unprocessed precursor form that can be purified and further studied. We also developed a cell-based reporter ass

SUBMITTER: Novotny P 

PROVIDER: S-EPMC11773056 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature