Virus and Cell Biology, Merck Research Labs, West Point, Pennsylvania, USA.
Curr Opin HIV AIDS. 2006 May;1(3):212-7. doi: 10.1097/01.COH.0000221594.57035.55.
The virally encoded enzyme integrase plays a critical role in HIV-1 replication and has long been considered a promising target for the development of agents to treat HIV-1 infection. It is only recently, however, that the efficacy of integrase inhibitors has been demonstrated in experimental animal model systems of retroviral infection, and in HIV-1 infected subjects. Several compounds that have shown potent efficacy in short-term monotherapy studies have initiated phase two and three clinical studies in 2006.
Although the first inhibitors in this new class of antiretroviral therapy are in the earliest stages of clinical development, the study of integrase function and inhibitor mechanism, as well as recent insights on resistance to prototypical inhibitors in vitro, have important implications for the discovery and development of these agents.
This review will summarize the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors, and the results of resistance studies on preclinical compounds which suggest there may be multiple opportunities for developing inhibitors against this essential HIV-1 target.
病毒编码的酶整合酶在 HIV-1 复制中起着关键作用，长期以来一直被认为是开发治疗 HIV-1 感染药物的有前途的靶点。然而，直到最近，整合酶抑制剂在实验性逆转录病毒感染动物模型系统和 HIV-1 感染患者中的疗效才得到证实。一些在短期单药治疗研究中显示出强大疗效的化合物于 2006 年启动了第二和第三阶段的临床研究。
尽管这一新类抗逆转录病毒治疗药物中的第一种抑制剂处于临床开发的早期阶段，但整合酶功能和抑制剂机制的研究，以及最近对体外原型抑制剂耐药性的研究结果，对这些药物的发现和开发具有重要意义。
本文综述了整合酶在 HIV-1 感染中的作用、整合酶抑制剂的作用机制，以及临床前化合物耐药性研究的结果，这些结果表明针对这一重要 HIV-1 靶点开发抑制剂可能有多种机会。
