Molecular design of AIDS therapeutics based on molecular recognition of enzymes.

基于底物-过渡态的概念，我们成功地设计和合成了一种高选择性和有效的HIV蛋白酶抑制剂（kni272）。KNI-272是根据HIV蛋白酶的作用机制合理设计的，具有较低的细胞毒性，可选择性地与HIV蛋白酶活性位点相互作用。这些结果强烈地引起了美国国家癌症研究所主任的注意，我们已经开始与那里的一个研究小组进行研究合作。为了进一步开展研究，我们对突变病毒和与突变酶配合的抗艾滋病药物进行了分子结构分析，并考虑到药酶相互作用，合理设计新型抗艾滋病药物。我们的研究结果被高度期待作为对抗耐药HIV的策略。我们的研究获得的化合物被认为是有前途的抗艾滋病药物，克服了副作用和耐药性。鉴定出对kni -272不敏感的病毒株。根据氨基酸序列，采用基因工程或化学方法合成了突变蛋白酶。我们分析了突变酶与抗艾滋病药物的相互作用，并检测了药物的活性构象。通过x射线晶体学、核磁共振和分子模型显示，强效抑制剂如kni272具有高度受限的构象。此外，在酶抑制剂相互作用分析的基础上，我们分析了参与相互作用的抑制剂的基本官能团。我们设计并合成了无耐药、无副作用的理想抗艾滋病药物——HIV蛋白酶抑制剂。获得了具有高抑制HIV蛋白酶活性的二肽衍生物。

Based on the substrate-transition state concept, we have succeeded to design and synthesize a highly selective and potent HIV protease inhibitor (KNI-272). Since KNI-272 was rationally designed based on the action mechanism of HIV protease, it exhibits low cytotoxicity and interacts selectively with HIV protease active site. These results strongly attracted the attention of the Directro of National Cancer Institute, U.S.A., and we have already started research collaboration with a research group there.In order to make a further progress of our research, we carried out the molecular structural analysis of mutant viruses and anti-AIDS drug complexed with mutant enzymes, and rationally designed novel anti-AIDS drugs considering the drug-enzyme interactions. The results of our research are highly expected as the strategy against resistant HIV.The compounds obtained by our research are considered as promising anti-AIDS drugs to overcome side effect and resistance.KNI-272-insensitive virus strains were identified. Based on the amino acid sequence, the mutated proteases were synthesized by genetic engineering or chemical methods. We analyzed the interaction between mutant enzymes and anti-AIDS drugs and examined the active conformation of the drugs. Potent inhibitors such as KNI-272 were shown to have highly constrained conformation by x-ray crystallography, NMR and molecular modeling.Furthermore, based on the analysis of enzyme-inhibitor interaction, we have analyzed the essential functional groups of the inhibitor participating in the interaction. We designed and synthesized HIV protease inhibitors aiming at ideal anti-AIDS drugs without resistance and side effects. Dipeptide derivatives with high HIV protease inhibiting activity were obtained.