Overcoming drug resistance in HIV-1 chemotherapy:: The binding thermodynamics of Amprenavir and TMC-126 to wild-type and drug-resistant mutants of the HIV-1 protease
Overcoming drug resistance in HIV-1 chemotherapy:: The binding thermodynamics of Amprenavir and TMC-126 to wild-type and drug-resistant mutants of the HIV-1 protease
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DOI：
10.1110/ps.0206402
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发表时间：
2002-08-01
期刊：
影响因子：
8
通讯作者：
Freire, E
中科院分区：
文献类型：
--
作者：
Ohtaka, H;Velázquez-Campoy, A;Freire, E
氨丙那韦是目前被批准用于艾滋病治疗的六种蛋白水解酶抑制剂之一。生化和临床研究表明，与其他抑制剂不同，氨丙那韦受到位于酶翻盖区域的蛋白酶突变150V的严重影响。TMC-126是第二代抑制剂，化学上与氨丙那韦有关，据报道，它对包括150V在内的现有耐药突变的敏感性极低。在本文中，我们研究了这两种抑制剂对影响所有现有临床抑制剂的150V突变和双活性位点突变V82F/184V的反应的热力学和分子起源。氨丙那韦以高亲和力(5.0×10(9)M-1或200 PM)与野生型HIV-1蛋白酶结合，这个过程同样受到焓和熵贡献的支持。突变150V和V82F/184V使氨丙那韦的结合亲和力分别降低147和104倍。另一方面，TMG-126以极高的结合亲和力(2.6×10(11)M~(-1)或3.9 PM)与野生型蛋白酶结合，结合过程中的焓贡献超过熵贡献近4倍。突变150V和V82F/184V使TMC-126的结合亲和力分别降低了16倍和11倍，表明TMC-126与耐药突变株的结合亲和力仍高于阿米那韦与野生型蛋白酶的亲和力。对TMC-126和另一种第二代抑制剂KNI-764的数据分析表明，它们对突变的低敏感性是因为它们能够通过更有利的结合熵来补偿与突变靶标相互作用的丧失，
Amprenavir is one of six protease inhibitors presently approved for clinical use in the therapeutic treatment of AIDS. Biochemical and clinical studies have shown that, unlike other inhibitors, Amprenavir is severely affected by the protease mutation 150V, located in the flap region of the enzyme. TMC-126 is a second-generation inhibitor, chemically related to Amprenavir, with a reported extremely low susceptibility to existing resistant mutations including 150V. In this paper, we have studied the thermodynamic and molecular origin of the response of these two inhibitors to the 150V mutation and the double active-site mutation V82F/184V that affects all existing clinical inhibitors. Amprenavir binds to the wild-type HIV-1 protease with high affinity (5.0 x 10(9) M-1 or 200 pM) in a process equally favored by enthalpic and entropic contributions. The mutations 150V and V82F/184V lower the binding affinity of Amprenavir by a factor of 147 and 104, respectively. TMG-126, on the other hand, binds to the wild-type protease with extremely high binding affinity (2.6 x 10(11) M-1 or 3.9 pM) in a process in which enthalpic contributions overpower entropic contributions by almost a factor of 4. The mutations 150V and V82F/184V lower the binding affinity of TMC-126 by only a factor of 16 and 11, respectively, indicating that the binding affinity of TMC-126 to the drug-resistant mutants is still higher than the affinity of Amprenavir to the wild-type protease. Analysis of the data for TMC-126 and KNI-764, another second-generation inhibitor, indicates that their low susceptibility to mutations is caused by their ability to compensate for the loss of interactions with the mutated target by a more favorable entropy of binding,