Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use
Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use
复制标题
DOI：
10.1111/j.1747-0285.2008.00647.x
复制
发表时间：
2008-04-01
影响因子：
3
通讯作者：
Freire, Ernesto
中科院分区：
文献类型：
--
作者：
Brower, Evan T.;Bacha, Usman M.;Freire, Ernesto
在过去的10年里，蛋白酶抑制剂一直是艾滋病毒/艾滋病抗逆转录病毒疗法的关键组成部分。虽然世界上绝大多数艾滋病毒/艾滋病病例是由艾滋病毒-1引起的，但也必须解决艾滋病毒-2感染问题。HIV-2是西非的地方病，也出现在葡萄牙、西班牙和爱沙尼亚等欧洲国家。目前的蛋白酶抑制剂还没有被优化用于治疗HIV-2感染；因此，评估目前FDA批准的蛋白酶抑制剂对HIV-2蛋白酶的有效性是很重要的，因为它与HIV-1蛋白酶只有50%的序列同源性。用动力学抑制法测定HIV-1酶抑制剂indinavir、nelfinavir、saquiavir、ritonavir、amprenavir、lopinavir、atazanavir、tipranavir和darunavir对HIV-2酶的抑制常数(K-I)。洛匹那韦、沙奎那韦、替普拉那韦和达鲁那韦的KI值分别为0.7、0.6、0.45和0.17 nM。这些Ki值比针对HIV-1蛋白酶的相应值弱84、2、24和17倍。一般来说，对于HIV-2和HIV-1蛋白酶，抑制剂显示的KI比率在2到80之间。效价的相对下降与抑制物对HIV-1蛋白酶的亲和力成正比，并与抑制物的特定结构特征有关。特别是，当缓蚀剂的最大帽尺寸由非常少的原子组成时，效力下降很高。帽是位于分子外围的基团，添加到核心结构中以增加抑制剂对其靶标的特异性。位于HIV-1蛋白酶抑制剂上的帽子通过与结合口袋的不同区域相互作用来影响选择性。大帽中较高数量的可旋转键赋予的灵活性和适应性使抑制剂能够适应HIV-1和HIV-2蛋白酶之间结合口袋几何形状的变化。
Over the past 10 years, protease inhibitors have been a key component in antiretroviral therapies for HIV/AIDS. While the vast majority of HIV/AIDS cases in the world are due to HIV-1, HIV-2 infection must also be addressed. HIV-2 is endemic to Western Africa, and has also appeared in European countries such as Portugal, Spain, and Estonia. Current protease inhibitors have not been optimized for treatment of HIV-2 infection; therefore, it is important to assess the effectiveness of currently FDA-approved protease inhibitors against the HIV-2 protease, which shares only 50% sequence identity with the HIV-1 protease. Kinetic inhibition assays were performed to measure the inhibition constants (K-i) of the HIV-1 protease inhibitors indinavir, nelfinavir, saquinavir, ritonavir, amprenavir, lopinavir, atazanavir, tipranavir, and darunavir against the HIV-2 protease. Lopinavir, saquinavir, tipranavir, and darunavir exhibit the highest potency with Ki values of 0.7, 0.6, 0.45, and 0.17 nM, respectively. These Ki values are 84, 2, 24, and 17 times weaker than the corresponding values against the HIV-1 protease. In general, inhibitors show Ki ratios ranging between 2 and 80 for the HIV-2 and HIV-1 proteases. The relative drop in potency is proportional to the affinity of the inhibitor against the HIV-1 protease and is related to specific structural characteristics of the inhibitors. In particular, the potency drop is high when the maximum cap size of the inhibitors consists of very few atoms. Caps are groups located at the periphery of the molecule that are added to core structures to increase the specificity of the inhibitor to its target. The caps positioned on the HIV-1 protease inhibitors affect selectivity through interactions with distinct regions of the binding pocket. The flexibility and adaptability imparted by the higher number of rotatable bonds in large caps enables an inhibitor to accommodate changes in binding pocket geometry between HIV-1 and HIV-2 protease.