二酮酸类HIV-1整合酶抑制剂研究进展

整合酶是HIV-1复制过程必需的酶,而人体不存在该酶的功能类似物,因而成为抗艾滋病药物设计的较理想靶点。本文综述了近年来二酮酸类整合酶抑制剂的发展现状,为寻找新型、高效的抗艾滋病药物提供参考。     

Closely related antiretroviral agents as inhibitors of two HIV-1 enzymes, ribonuclease H and integrase: "killing two birds with one stone"

The structures of the catalytic core of two HIV-1 encoded enzymes play a crucial role in the retroviral cycle: integrase and RNase H exhibit striking similarities. These enzymes also share a similar mechanism of catalysis. The homologies between RNase H and integrase led to studying the effect of the RNase H inhibitors on integrase. ODNs aptamers active on RNase H were shown to be strong IN inhibitors. On the contrary, compounds from the diketo acid family were previously known as integrase inhibitors. One compound of this family is able to inhibit the RNase H activity, but has no effect on integrase. Cellular topoisomerase 1 also shares a mechanism similar to that of HIV-1 integrase and RNase H. It has been reported to be present in retroviral particles and to enhance cDNA synthesis. Some topoisomerase inhibitors have been shown to be active on integrase. Moreover, topoisomerase, integrase and RNase H are inhibited by G-rich oligonucleotides. A G-quartet structure is necessary for integrase, but not for topoisomerase inhibition. This suggests that prototype structures can be exploited to develop inhibitors of two related enzymes, such as the RNase H and integrase activities of HIV-1 RT.