Novel azapeptide inhibitors of hepatitis C virus serine protease

Journal of Medicinal Chemistry
Murray BaileyM Llinàs-Brunet

Abstract

Azapeptides are known inhibitors of several serine and cysteine proteases. In seeking different classes of inhibitors for the HCV serine protease, a series of novel azapeptide-based inhibitors were investigated which incorporated noncleavable P1/P1' aza-amino acyl residues. Extensive SAR studies around the P1/P1' aza-amino acyl fragment resulted in the identification of potent and selective inhibitors. Using NMR studies, we have shown that this series of inhibitors bind in a noncovalent competitive fashion to the NS3 protease active site. The bound conformation of one of these new azapeptide-based inhibitors was determined using the transfer NOE technique. Incorporation of these new aza-amino acyl functionalities in the P1 position provided a handle to probe for new interactions in the S' region of the enzyme.

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Citations

Aug 3, 2011·Future Medicinal Chemistry·Caroline ProulxWilliam D Lubell
Sep 8, 2005·Expert Opinion on Investigational Drugs·Nathalie Goudreau, Montse Llinàs-Brunet
Mar 3, 2012·Journal of Enzyme Inhibition and Medicinal Chemistry·Ivana PerkovićBranka Zorc
Feb 2, 2017·Beilstein Journal of Organic Chemistry·Angélica de Fátima S BarretoCarlos Kleber Z Andrade
Jul 8, 2018·Nature Communications·Yuchao ZhuNing Jiao
May 17, 2005·Bioorganic & Medicinal Chemistry·Jon BondebjergLars Naerum
Apr 14, 2010·Chemical Reviews·Wendy A LoughlinDavid P Fairlie

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