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药物的引入，为艾滋病的联合治疗提供了新的发展方向。但在剂量、经济、副作用、耐药、转运到中枢神经系统等方面仍有许多问题有待解决。为了克服这些问题，我们根据核磁共振结构分析和分子模型研究的数据，设计并合成了含有羟甲基羰基（HHMC）等异构体和理想过渡态模拟物的小尺寸HIV蛋白酶抑制剂。小尺寸和高效的抑制剂在成本和耐药诱导方面都是有利的，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能表现出更好的组织运输，改善药代动力学，并且可以在较低剂量下使用。这些结果表明含有hmc的描述抑制剂作为下一代HIV蛋白酶抑制剂有希望用于联合治疗。O-N酰基迁移型HIV蛋白酶抑制剂前药具有较好的溶解度和生物利用度，表现出优异的细胞膜渗透性和细胞内生成成分对HIV复制不同靶点的协同作用。这种新型杂交药物有望成为一种耐药、可克服的新型抗艾滋病药物。

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.