Markowitz M, Mo H, Kempf D J, Norbeck D W, Bhat T N, Erickson J W, Ho D D
Aaron Diamond AIDS Research Center, New York University School of Medicine, New York 10016.
J Virol. 1995 Feb;69(2):701-6. doi: 10.1128/JVI.69.2.701-706.1995.
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 next generation of protease inhibitors.
人类免疫缺陷病毒蛋白酶抑制剂是一类很有前景的新型抗逆转录病毒药物，用于治疗艾滋病。我们现在报告了对一种基于对称结构的蛋白酶抑制剂ABT - 538敏感性降低的病毒变体的体外筛选情况，该抑制剂目前正在临床试验中进行测试。对这些变体的分子特征分析表明，84位的异亮氨酸到缬氨酸的替换导致对该药物的敏感性大幅降低。此外，82位的缬氨酸到苯丙氨酸的额外突变进一步降低了病毒对ABT - 538的敏感性。蛋白酶 - 药物复合物的三维分析为这两个突变所诱导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治疗的患者是否出现病毒耐药性的重要性，并提供了可能有助于设计下一代蛋白酶抑制剂的信息。
