8FIW

Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun10221

Summary for 8FIW

• Entry DOI: 10.2210/pdb8fiw/pdb
• Descriptor: 3C-like proteinase nsp5, N-([1,1'-biphenyl]-4-yl)-N-[(1R)-2-oxo-2-{[(1S)-1-phenylethyl]amino}-1-(pyridin-3-yl)ethyl]prop-2-enamide, N-([1,1'-biphenyl]-4-yl)-N-[(1S)-2-oxo-2-{[(1S)-1-phenylethyl]amino}-1-(pyridin-3-yl)ethyl]prop-2-enamide (3 entities in total)
• Functional Keywords: sars-cov-2 mpro, main protease, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 69035.76

Authors

Sacco, M.,Wang, J.,Chen, Y. (deposition date: 2022-12-16, release date: 2023-08-09, Last modification date: 2024-11-06)

Primary citation

Tan, B.,Sacco, M.,Tan, H.,Li, K.,Joyce, R.,Zhang, X.,Chen, Y.,Wang, J.
Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.
Eur.J.Med.Chem., 259:115667-115667, 2023

PubMed Abstract: SARS-CoV-2 main protease (M) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant M mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of M inhibitors. In this study, we explored several reactive warheads in the design of M inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent M inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC values of 2.92 and 6.47 μM, respectively. X-ray crystal structures of M with Jun10541R and Jun10221 revealed covalent modification of Cys145. These M inhibitors with diverse reactive warheads collectively represent promising candidates for further development.

PubMed: 37482021
DOI: 10.1016/j.ejmech.2023.115667

Experimental method

X-RAY DIFFRACTION (2.54 Å)