Design and synthesis of irreversible inhibitors of foot-and-mouth disease virus 3C protease

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Rosell, Nuria R. Roque¹  Mokhlesi, Ladan¹  Milton, Nicholas E.¹  Sweeney, Trevor R.²  Zunszain, Patricia A.²  Curry, Stephen²  Leatherbarrow, Robin J.^1,3 

[1] Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England

[2] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, London SW7 2AZ, England

[3] Liverpool John Moores Univ, Liverpool L1 2UA, Merseyside, England

关键词: Foot-and-mouth disease virus;    3C protease;    Cysteine protease;    Warhead;    Irreversible inhibitor;   

DOI  :  10.1016/j.bmcl.2013.12.045

来源: Elsevier

【 摘 要 】

Foot-and-mouth disease virus (FMDV) causes a highly infectious and economically devastating disease of livestock. The FMDV genome is translated as a single polypeptide precursor that is cleaved into functional proteins predominantly by the highly conserved viral 3C protease, making this enzyme an attractive target for antiviral drugs. A peptide corresponding to an optimal substrate has been modified at the C-terminus, by the addition of a warhead, to produce irreversible inhibitors that react as Michael acceptors with the enzyme active site. Further investigation highlighted key structural determinants for inhibition, with a positively charged P2 being particularly important for potency. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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