Molecular design of HIV protease inhibitors restricted to active conformation

具有新作用机制的HIV蛋白酶抑制剂作为抗HIV药物的出现，为艾滋病的综合治疗提供了新的发展方向。为了克服这些问题，我们在NMR结构分析和分子模拟研究的基础上，设计合成了含有羟甲基羰基（HHMC）等排体和理想过渡态模拟物的小分子HIV蛋白酶抑制剂。小尺寸和高效力的抑制剂在成本和抗性诱导方面是有利的，因为分子识别研究表明这些抑制剂在较少的位点与酶相互作用。此外，较小尺寸的抑制剂可以表现出更好的组织运输，改善的药代动力学，并且可以以较低剂量使用。O-N酰基迁移型HIV蛋白酶抑制剂前体药物具有较好的溶解性和生物利用度，表现出良好的细胞膜渗透性和细胞内生成组分协同作用于HIV复制过程中不同靶点的协同效应。这种新型的杂交型药物有望成为一种新型的耐药性可克服的抗艾滋病药物。

Introduction of HIV protease inhibitors with new action mechanism as anti-HIV drugs provided a new development in the combination therapy of AIDS. However, there are many problems to be solved such as dose, economics, side effects, resistance, transport to central nervous system.In order to overcome these problems, we designed and synthesized small-sized HIV protease inhibitors containing hydroxymethlcarbonyl (HHMC) isostere, and ideal transition state mimic, based on the data obtained from NMR structural analysis and molecular modeling studies. Inhibitors of small size and high potency are advantageous in terms of cost, and resistance induction as well, because molecular recognition studies showed that these inhibitors interacts with the enzyme at fewer sites. Furthermore, smaller-sized inhibitors may exhibit better tissue transportation, improved pharmacokinetics and may be usable at lower dose. These results indicate that HMC-containing depicted inhibitors are promising for combination therapy as HIV protease inhibitors of next generation.O-N Acyl migration-type prodrug of HIV protease inhibitors exhibited better solubility and improved bioavailability, which shows excellent cell membrane permeability and synergistic effect acting on the different targets in HIV replication by intracellularly generated components. This new hybrid type drugs are expected as a new type of resistance surmountable anti-AIDS agents.