Joint Study on AIDS Drug Based on HIV Protease

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We have designed and synthesized a highly selective and potent HIV protease inhibitor (KNI-272) based on the substrate transition state concept of HIV protease. KNI-272 exhibits low cytotoxicity, specifically interacts with the HIV protease active site, because it was rationally designed based on the reaction mechanism of HIV protease, and thus is expected to be an ideal anti-AIDS drug. Therefore, starting from these results, the analysis of the interaction of KNI-272 with HIV protease showed that KNI-272 has constrained conformation and is an ideal transition state mimic.Furthermore, we carried out the molecular structural analysis of mutant HIV protease and rationally designed a series of new anti-HIV drugs based on the interaction between mutant enzyme and inhibitors.In the mutant HIV and HIV-2, their HIV protease have low enzymatic activity. Furthermore, it is reported that mutant HIV exhibits low infectivity and HIV-2 has low pathogenicity. These facts implies that low enzymatic activity is one of the causes of low infectivity. We made approach at chemical structure level of enzymes to molecular mechanism analysis of viral pathogenicity. As a result, we have found small sized dipeptide HIV protease inhibitors, KNI-413 and KNI-549. In addition, we designed KNI-241 and smaller-sized KNI-727 which are active against HIV-1 resistant to KNI-272.This research on HIV protease inhibitors was rationally carried out based on the structural analysis of the complex of the enzyme and the inhibitor, and is regarded to establish the methodology to control the drug resistance of HIV.