SARS-CoV-2 is the coronavirus pathogen of the currently prevailing COVID-19 pandemic. It relies on its main protease (MPro) for replication and pathogenesis. MPro is a demonstrated target for the development of antivirals for SARS-CoV-2. MPro recognizes protein substrates with their P1 residue strictly as glutamine. A straightforward approach to develop MPro inhibitors is to change the P1 C-terminal backbone amide in substrates to aldehyde that forms a reversible covalent hemithioacetal adduct with MPro C145. Based on this design, we made series of peptidyl compounds for MPro inhibition testing, and starting from which carried out SAR studies, which resulted in over a hundred compounds synthesized and tested, some of them having nM level IC50, EC50 or antiviral potency. To screen MPro inhibitors, we developed a protocol to use sub3, a fluorogenic peptide substrate of MPro to determine IC50 values for all synthesized compounds. Noticing main protease (MPro) triggers acute toxicity to its human cell host, we developed an effective method that allows a bulk analysis of the cellular potency of MPro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular MPro inhibition information to assess an MPro inhibitor. For some compounds, an antiviral assay was also carried out using ACE2+ A549 cells to compare with the cellular assay data. The study gives us an insight of the mechanism of Mpro and some potential drug candidate for SARS-CoV-2.

Systematic study for SARS-CoV-2 main protease inhibitors

Where thousands of chemistry professionals meet to share ideas and advance scientific and technical knowledge. Spring 2023 abstracts, posters, and presentations will launch at the end of March.

ACS Spring 2023

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.