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    Quinoxaline-Based Linear HCV NS3/4A Protease Inhibitors Exhibit Potent Activity against Drug Resistant Variants

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    Authors
    Rusere, Linah
    Matthew, Ashley N.
    Lockbaum, Gordon J.
    Jahangir, Muhammad
    Newton, Alicia
    Petropoulos, Christos J.
    Huang, Wei
    Yilmaz, Nese Kurt
    Schiffer, Celia A.
    Ali, Akbar
    UMass Chan Affiliations
    Graduate School of Biomedical Sciences, MD/PhD Program
    Schiffer Lab
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2018-05-17
    Keywords
    crystal structure
    drug resistance
    HCV
    NS3/4A protease
    protease inhibitor quinoxaline
    Biochemistry
    Chemistry
    Heterocyclic Compounds
    Medicinal Chemistry and Pharmaceutics
    Medicinal-Pharmaceutical Chemistry
    Molecular Biology
    Pharmacology
    Structural Biology
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    Link to Full Text
    https://doi.org/10.1021/acsmedchemlett.8b00150
    Abstract
    A series of linear HCV NS3/4A protease inhibitors was designed by eliminating the P2-P4 macrocyclic linker in grazoprevir, which, in addition to conferring conformational flexibility, allowed structure-activity relationship (SAR) exploration of diverse quinoxalines at the P2 position. Biochemical and replicon data indicated preference for small hydrophobic groups at the 3-position of P2 quinoxaline for maintaining potency against resistant variants R155K, A156T, and D168A/V. The linear inhibitors, though generally less potent than the corresponding macrocyclic analogues, were relatively easier to synthesize and less susceptible to drug resistance. Three inhibitor cocrystal structures bound to wild-type NS3/4A protease revealed a conformation with subtle changes in the binding of P2 quinoxaline, depending on the 3-position substituent, likely impacting both inhibitor potency and resistance profile. The SAR and structural analysis highlight inhibitor features that strengthen interactions of the P2 moiety with the catalytic triad residues, providing valuable insights to improve potency against resistant variants.
    Source

    ACS Med Chem Lett. 2018 May 17;9(7):691-696. doi: 10.1021/acsmedchemlett.8b00150. eCollection 2018 Jul 12. Link to article on publisher's site

    DOI
    10.1021/acsmedchemlett.8b00150
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/48876
    PubMed ID
    30034602
    Related Resources

    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1021/acsmedchemlett.8b00150
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    Morningside Graduate School of Biomedical Sciences Scholarly Publications
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