8fiv

Crystal structure of the SARS-CoV-2 (COVID-19) main protease in complex with inhibitor Jun10541R

spinqualitylabelsall models 8fiv, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fiv is a 1 chain structure with sequence from Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.51Å Ligands: Y0I Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed SARS-CoV-2 main protease (M(pro)) 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(pro) 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(pro) inhibitors. In this study, we explored several reactive warheads in the design of M(pro) 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(pro) inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC(50) values of 2.92 and 6.47 muM, respectively. X-ray crystal structures of M(pro) with Jun10541R and Jun10221 revealed covalent modification of Cys145. These M(pro) inhibitors with diverse reactive warheads collectively represent promising candidates for further development. Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.,Tan B, Sacco M, Tan H, Li K, Joyce R, Zhang X, Chen Y, Wang J Eur J Med Chem. 2023 Nov 5;259:115667. doi: 10.1016/j.ejmech.2023.115667. Epub , 2023 Jul 19. PMID:37482021 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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