Klarmann George J, Hawkins Mary E, Le Grice Stuart F J
Reverse Transcriptase Biochemistry Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, P.O. Box B Frederick, MD 21702, USA.
AIDS Rev. 2002 Oct-Dec;4(4):183-94.
Successful long-term management of HIV infection will require targeted inhibition of multiple steps essential for virus replication. Currently, both nucleoside- and nonnucleoside-based inhibitors of DNA polymerase function, in combination with antagonists of HIV protease, have been shown to be clinically beneficial. However, it is clear that RNase H activity of the multifunctional HIV-1 reverse transcriptase (RT) is absolutely required for completion of retroviral DNA synthesis, thereby rendering this function an attractive target for drug development. Although generally viewed as a sequence-independent activity, highly precise RNase H cleavage is required in order to remove the RNA primers of (-) and (+) strand DNA synthesis (a host-derived tRNA and the polypurine tract, respectively), thereby preserving the ends of linear DNA and facilitating integration. The availability of highly purified, recombinant RT/RNase H has allowed a thorough dissection of these multiple events and their potential for therapeutic intervention. Our current understanding of retroviral RNase H function and the status of small molecule inhibitors are the focus of this review.
成功地长期管理HIV感染将需要靶向抑制病毒复制所必需的多个步骤。目前，基于核苷和非核苷的DNA聚合酶功能抑制剂与HIV蛋白酶拮抗剂联合使用已显示出临床益处。然而，很明显，多功能HIV-1逆转录酶（RT）的RNase H活性对于完成逆转录病毒DNA合成绝对必要，从而使该功能成为药物开发的一个有吸引力的靶点。尽管通常被视为一种不依赖序列的活性，但为了去除（-）和（+）链DNA合成的RNA引物（分别是宿主来源的tRNA和多聚嘌呤序列），需要高度精确的RNase H切割，从而保留线性DNA的末端并促进整合。高纯度重组RT/RNase H的可得性使得对这些多个事件及其治疗干预潜力进行了彻底剖析。我们目前对逆转录病毒RNase H功能的理解以及小分子抑制剂的现状是本综述的重点。
