Perni Robert B, Almquist Susan J, Byrn Randal A, Chandorkar Gurudatt, Chaturvedi Pravin R, Courtney Lawrence F, Decker Caroline J, Dinehart Kirk, Gates Cynthia A, Harbeson Scott L, Heiser Angela, Kalkeri Gururaj, Kolaczkowski Elaine, Lin Kai, Luong Yu-Ping, Rao B Govinda, Taylor William P, Thomson John A, Tung Roger D, Wei Yunyi, Kwong Ann D, Lin Chao
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA.
Antimicrob Agents Chemother. 2006 Mar;50(3):899-909. doi: 10.1128/AAC.50.3.899-909.2006.
VX-950 is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A serine protease, and it demonstrated excellent antiviral activity both in genotype 1b HCV replicon cells (50% inhibitory concentration [IC50] = 354 nM) and in human fetal hepatocytes infected with genotype 1a HCV-positive patient sera (IC50 = 280 nM). VX-950 forms a covalent but reversible complex with the genotype 1a HCV NS3-4A protease in a slow-on, slow-off process with a steady-state inhibition constant (K(i)*) of 7 nM. Dissociation of the covalent enzyme-inhibitor complex of VX-950 and genotype 1a HCV protease has a half-life of almost an hour. A >4-log10 reduction in the HCV RNA levels was observed after a 2-week incubation of replicon cells with VX-950, with no rebound of viral RNA observed after withdrawal of the inhibitor. In several animal species, VX-950 exhibits a favorable pharmacokinetic profile with high exposure in the liver. In a recently developed HCV protease mouse model, VX-950 showed excellent inhibition of HCV NS3-4A protease activity in the liver. Therefore, the overall preclinical profile of VX-950 supports its candidacy as a novel oral therapy against hepatitis C.
VX - 950是一种强效、选择性的丙型肝炎病毒（HCV）NS3 - 4A丝氨酸蛋白酶拟肽抑制剂，它在1b型HCV复制子细胞（50%抑制浓度[IC50]=354 nM）和感染1a型HCV阳性患者血清的人胎肝细胞中均表现出优异的抗病毒活性（IC50 = 280 nM）。VX - 950在一个慢结合、慢解离的过程中与1a型HCV NS3 - 4A蛋白酶形成共价但可逆的复合物，其稳态抑制常数（K(i)*）为7 nM。VX - 950与1a型HCV蛋白酶的共价酶 - 抑制剂复合物的解离半衰期近一小时。用VX - 950孵育复制子细胞2周后，观察到HCV RNA水平降低了>4个对数10，在撤去抑制剂后未观察到病毒RNA反弹。在几种动物物种中，VX - 950表现出良好的药代动力学特征，在肝脏中有高暴露。在最近开发的HCV蛋白酶小鼠模型中，VX - 950在肝脏中对HCV NS3 - 4A蛋白酶活性表现出优异的抑制作用。因此，VX - 950的整体临床前特征支持其作为一种新型抗丙型肝炎口服疗法的候选资格。
