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

基于底物-过渡态的概念，我们成功地设计并合成了一种高选择性的HIV蛋白酶抑制剂（KNI-272）。由于KNI-272是根据HIV蛋白酶的作用机制进行合理设计的，因此它具有低细胞毒性，并选择性地与HIV蛋白酶活性位点相互作用。这些结果引起了美国国家癌症研究所主任的高度重视，为了使我们的研究取得更大的进展，我们进行了突变病毒和抗艾滋病药物与突变酶复合物的分子结构分析，并考虑药物-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望作为对抗耐药性HIV的策略。我们的研究所获得的化合物被认为是有希望的抗艾滋病药物，以克服副作用和耐药性。基于氨基酸序列，通过基因工程或化学方法合成突变蛋白酶。我们分析了突变酶与抗艾滋病药物之间的相互作用，并检测了药物的活性构象。通过X射线晶体学、核磁共振和分子模拟等方法，发现KNI-272等抑制剂具有高度的构象约束，并在此基础上分析了抑制剂与酶的相互作用，分析了抑制剂中参与相互作用的重要官能团。本课题以寻找理想的无耐药性、无副作用的抗艾滋病药物为目标，设计合成了HIV蛋白酶抑制剂。获得了具有高HIV蛋白酶抑制活性的二肽衍生物。

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.