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和高效的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，因此它具有低的细胞毒性，并选择性地与HIV酶活性部位相互作用。这些结果引起了美国国家癌症研究所的高度重视，我们已经与那里的一个研究小组开始了研究合作。为了进一步推进我们的研究，我们对突变病毒和与突变酶复合的抗艾滋病药物进行了分子结构分析，并考虑到药物与酶的相互作用，合理设计了抗艾滋病新药。我们的研究结果被认为是对抗耐药HIV的策略。我们的研究得到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。对KNI-272不敏感病毒株进行了鉴定。根据氨基酸序列，通过基因工程或化学方法合成突变的蛋白水解酶。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。X-射线结晶学、核磁共振和分子模拟表明，KNI-272等强效抑制剂具有高度的限制性构象。此外，在分析酶-抑制剂相互作用的基础上，我们分析了参与相互作用的抑制剂的基本官能团。针对理想的无耐药性、无毒副作用的抗艾滋病药物，设计合成了HIV蛋白水解酶抑制剂。得到了具有较高HIV酶抑制活性的二肽类化合物。

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.