Bailey Murray D, Halmos Ted, Goudreau Nathalie, Lescop Ewen, Llinàs-Brunet Montse
Boehringer Ingelheim (Canada) Ltd. Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5.
J Med Chem. 2004 Jul 15;47(15):3788-99. doi: 10.1021/jm049864b.
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.
氮杂肽是几种丝氨酸和半胱氨酸蛋白酶的已知抑制剂。在寻找丙型肝炎病毒丝氨酸蛋白酶的不同类型抑制剂时，研究了一系列基于氮杂肽的新型抑制剂，这些抑制剂含有不可裂解的P1/P1'氮杂氨基酰基残基。围绕P1/P1'氮杂氨基酰基片段进行的广泛构效关系研究，鉴定出了强效且选择性的抑制剂。通过核磁共振研究，我们表明这一系列抑制剂以非共价竞争方式结合到NS3蛋白酶活性位点。使用转移核Overhauser效应（transfer NOE）技术确定了其中一种新型基于氮杂肽的抑制剂的结合构象。在P1位置引入这些新的氮杂氨基酰基官能团，为探索酶的S'区域中的新相互作用提供了一种手段。
