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Chemical Structure| 848133-35-7 Chemical Structure| 848133-35-7
Chemical Structure| 848133-35-7

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CAS No.: 848133-35-7

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Khatua, Kaustav ; Alugubelli, Yugendar R. ; Yang, Kai S. ; Vulupala, Veerabhadra R. ; Blankenship, Lauren R. ; Coleman, Demonta D. , et al.

Abstract: Main protease (MPro) of SARS-CoV-2, the viral pathogen of COVID-19, is a crucial nonstructural protein that plays a vital role in the replication and pathogenesis of the virus. Its protease function relies on three active site pockets to recognize P1, P2, and P4 amino acid residues in a substrate and a catalytic cysteine residue for catalysis. By converting the P1 Cα atom in an MPro substrate to nitrogen, we showed that a large variety of azapeptide inhibitors with covalent warheads targeting the MPro catalytic cysteine could be easily synthesized. Through the characterization of these inhibitors, we identified several highly potent MPro inhibitors. Specifically, one inhibitor, MPI89 that contained an aza-2,2-dichloroacetyl warhead, displayed a 10 nM EC50 value in inhibiting SARS-CoV-2 from infecting ACE2+ A549 cells and a selectivity index of 875. The crystallog. analyses of MPro bound with 6 inhibitors, including MPI89, revealed that inhibitors used their covalent warheads to covalently engage the catalytic cysteine and the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 represents one of the most potent MPro inhibitors developed so far, suggesting that further exploration of the azapeptide platform and the aza-2,2-dichloroacetyl warhead is needed for the development of potent inhibitors for the SARS-CoV-2 MPro as therapeutics for COVID-19.

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Product Details of [ 848133-35-7 ]

CAS No. :848133-35-7
Formula : C6H12ClNO2
M.W : 165.62
SMILES Code : O=C(O)/C=C/CN(C)C.[H]Cl
MDL No. :MFCD03695466
InChI Key :UUHNQHFOIVLAQX-BJILWQEISA-N
Pubchem ID :45358758

Safety of [ 848133-35-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338
 

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