7XAR

Crystal structure of 3C-like protease from SARS-CoV-2 in complex with covalent inhibitor

Summary for 7XAR

• Entry DOI: 10.2210/pdb7xar/pdb
• Descriptor: 3C-like proteinase, NICKEL (II) ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: 3c-like proteinase, main protease, sars-cov-2, chlorofluoroacetamides, targeted covalent inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68942.42

Authors

Caaveiro, J.M.M.,Ochi, J.,Takahashi, D.,Ueda, T.,Ojida, A. (deposition date: 2022-03-18, release date: 2022-11-09, Last modification date: 2023-11-29)

Primary citation

Hirose, Y.,Shindo, N.,Mori, M.,Onitsuka, S.,Isogai, H.,Hamada, R.,Hiramoto, T.,Ochi, J.,Takahashi, D.,Ueda, T.,Caaveiro, J.M.M.,Yoshida, Y.,Ohdo, S.,Matsunaga, N.,Toba, S.,Sasaki, M.,Orba, Y.,Sawa, H.,Sato, A.,Kawanishi, E.,Ojida, A.
Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease.
J.Med.Chem., 65:13852-13865, 2022

PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 3C-like protease (3CL) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CL that possess chlorofluoroacetamide (CFA) as a cysteine-reactive warhead. Based on an aza-peptide scaffold, we synthesized a series of CFA derivatives in enantiopure form and evaluated their biochemical efficiency. The data revealed that () with the configuration at the CFA unit strongly blocks SARS-CoV-2 replication in infected cells, and its potency is comparable to that of nirmatrelvir. X-ray structural analysis showed that formed a covalent bond with Cys145 at the catalytic center of 3CL. The strong antiviral activity and favorable pharmacokinetic properties of suggest its potential as a lead compound for the treatment of COVID-19.

PubMed: 36229406
DOI: 10.1021/acs.jmedchem.2c01081

Experimental method

X-RAY DIFFRACTION (1.6 Å)