SELECTION AND ANALYSIS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-I VARIANTS WITH INCREASED RESISTANCE TO ABT-538, A NOVEL PROTEASE INHIBITOR
SELECTION AND ANALYSIS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-I VARIANTS WITH INCREASED RESISTANCE TO ABT-538, A NOVEL PROTEASE INHIBITOR
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DOI：
10.1128/jvi.69.2.701-706.1995
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发表时间：
1995-02-01
影响因子：
5.4
通讯作者：
HO, DD
中科院分区：
文献类型：
--
作者：
MARKOWITZ, M;MO, HM;HO, DD
人类免疫缺陷病毒蛋白水解酶的抑制剂代表了一类很有前途的治疗艾滋病的新型抗逆转录病毒药物。我们现在报告对对基于对称的蛋白酶抑制剂ABT-538敏感性降低的病毒变体的体外选择，目前正在进行临床试验。对变异体的分子表征表明，第84位的异亮氨酸到缬氨酸的取代导致对药物的敏感性显著降低。此外，第82位的一个额外突变，Valine到苯丙氨酸，进一步降低了病毒对ABT-538的易感性。对蛋白酶-药物复合体的三维分析为这两个突变引起的相对耐药性提供了结构上的解释。这些发现强调了密切监测接受ABT-538治疗的患者出现病毒耐药性的重要性，并提供了可能被证明对设计下一代蛋白酶抑制剂有用的信息。
Inhibitors of the human immunodeficiency virus protease represent a promising new class of antiretroviral drugs for the treatment of AIDS. We now report the in vitro selection of viral variants with decreased sensitivity to a symmetry-based protease inhibitor, ABT-538, currently being tested in clinical trials. Molecular characterization of the variants shows that an isoleucine-to-valine substitution at position 84 results in a substantial decrease in sensitivity to the drug. Moreover, an additional mutation at position 82, valine to phenylalanine, further decreases viral susceptibility to ABT-538. Three-dimensional analysis of the protease-drug complex provides a structural explanation for the relative drug resistance induced by these two mutations. These findings emphasize the importance of closely monitoring patients receiving ABT-538 for the emergence of viral resistance and provide information that may prove useful in designing the nest generation of protease inhibitors.