8FY6

SARS-CoV-2 main protease in complex with covalent inhibitor

Summary for 8FY6

• Entry DOI: 10.2210/pdb8fy6/pdb
• Descriptor: 3C-like proteinase nsp5, (1R,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-N-{(2R)-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: sars-cov-2 main protease, protease, non-structural protein, covalent inhibitor, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34328.12

Authors

Fried, W.,Chen, X.S. (deposition date: 2023-01-25, release date: 2023-08-30, Last modification date: 2024-10-23)

Primary citation

Ngo, C.,Fried, W.,Aliyari, S.,Feng, J.,Qin, C.,Zhang, S.,Yang, H.,Shanaa, J.,Feng, P.,Cheng, G.,Chen, X.S.,Zhang, C.
Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.
J.Med.Chem., 66:12237-12248, 2023

PubMed Abstract: There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of M. By comparing the efficacy of a panel of warheads installed on a common scaffold against M, we discovered that the terminal alkyne could covalently modify M as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of M. Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.

PubMed: 37595260
DOI: 10.1021/acs.jmedchem.3c00810

Experimental method

X-RAY DIFFRACTION (2 Å)