Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
ACS Infect Dis. 2024 Mar 8;10(3):917-927. doi: 10.1021/acsinfecdis.3c00525. Epub 2024 Feb 12.
HIV-1 integrase (IN) is an important molecular target for the development of anti-AIDS drugs. A recently FDA-approved second-generation integrase strand transfer inhibitor (INSTI) cabotegravir (CAB, 2021) is being marketed for use in long-duration antiviral formulations. However, missed doses during extended therapy can potentially result in persistent low levels of CAB that could select for resistant mutant forms of IN, leading to virological failure. We report a series of -substituted bicyclic carbamoyl pyridones (BiCAPs) that are simplified analogs of CAB. Several of these potently inhibit wild-type HIV-1 in single-round infection assays in cultured cells and retain high inhibitory potencies against a panel of viral constructs carrying resistant mutant forms of IN. Our lead compound, , proved to be more potent than CAB against the therapeutically important resistant double mutants E138K/Q148K (>12-fold relative to CAB) and G140S/Q148R (>36-fold relative to CAB). A significant number of the BiCAPs also potently inhibit the drug-resistant IN mutant R263K, which has proven to be problematic for the FDA-approved second-generation INSTIs.
HIV-1 整合酶（IN）是开发抗艾滋病药物的重要分子靶标。最近美国食品和药物管理局（FDA）批准的第二代整合酶链转移抑制剂（INSTI）卡博特韦（CAB，2021 年）正在作为长效抗病毒制剂上市。然而，在延长治疗期间漏服可能会导致 CAB 持续低水平，从而选择出具有耐药突变形式的 IN，导致病毒学失败。我们报告了一系列 -取代的双环氨基甲酰基吡啶酮（BiCAPs），它们是 CAB 的简化类似物。这些类似物中的几种在培养细胞中的单次感染试验中对野生型 HIV-1 具有很强的抑制作用，并对携带 IN 耐药突变体的一系列病毒构建体保持高抑制效力。我们的先导化合物 ，对治疗上重要的耐药双突变体 E138K/Q148K（相对于 CAB 高出 12 倍）和 G140S/Q148R（相对于 CAB 高出 36 倍）的抑制作用比 CAB 更强。相当数量的 BiCAPs 也能强烈抑制耐药 IN 突变体 R263K，这对 FDA 批准的第二代 INSTIs 来说是一个问题。
