Department of Chemistry -- BMC, Uppsala University , Uppsala , Sweden and.
J Enzyme Inhib Med Chem. 2014 Dec;29(6):868-76. doi: 10.3109/14756366.2013.864651. Epub 2014 Feb 11.
Natural strain variation and rapid resistance development makes development of broad spectrum hepatitis C virus (HCV) drugs very challenging and evaluation of inhibitor selectivity and resistance must account for differences in the catalytic properties of enzyme variants.
To understand how to study selectivity and relationships between efficacy and genotype or resistant mutants for NS3 protease inhibitors.
The catalytic properties of NS3 protease from genotypes 1a, 1b and 3a, and their sensitivities to four structurally and mechanistically different NS3 protease inhibitors have been analysed under different experimental conditions.
The optimisation of buffer conditions for each protease variant enabled the comparison of their catalytic properties and sensitivities to the inhibitors. All inhibitors were most effective against genotype 1a protease, with VX-950 having the broadest selectivity.
A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.
天然菌株变异和快速耐药性的发展使得广谱丙型肝炎病毒（HCV）药物的开发极具挑战性，并且必须考虑到酶变体催化特性的差异，来评估抑制剂的选择性和耐药性。
了解如何研究 NS3 蛋白酶抑制剂的选择性以及疗效与基因型或耐药突变体之间的关系。
分析了基因型 1a、1b 和 3a 的 NS3 蛋白酶的催化特性及其对四种结构和作用机制不同的 NS3 蛋白酶抑制剂的敏感性，在不同的实验条件下进行。
通过优化每种蛋白酶变体的缓冲条件，可以比较它们的催化特性和对抑制剂的敏感性。所有抑制剂对基因型 1a 蛋白酶的效果最佳，VX-950 的选择性最广。
建立了一种评估广谱 HCV 药物发现相关抑制剂的新策略。
