Joint study on protease-targeted anti-AIDS drugs

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The HIV codes for a virus-specific aspartic protease responsible for processing the gag and gag-pol polyproteons and for the proliferation of the retrovirus. The HIV protease is considered as a potential target for the development of anti-AIDS agents.Based on the substrate transition-state mimic concept and Phe-Pro as the virus specific cleavage sequence, we designed and synthesized a novel class of HIV protease inhibitors containing an unnatural amino acid, allophenylnorstatine (Apns) as a hydroxymethylcarbonyl isostere.After lead optimization study, the most excellent tripeptide inhibitor, kynostatin (KNI)-272 was adopted as the candidate for pharmacokinetic and clinical study. This year, we have carried out the following studies for the development of KNI-272 as an anti-HIV drug.1.Preparation of a prodrug and large-scale synthesis of KNI-272. A water-soluble prodrug which is transformed to an active-form in vivo by intramolecular N-O acyl rearrangement was prepared. A highly efficie … More nt and stereoselective large-scale synthesis of KNI-272 was established for the pharmacokinetic study.2.Synthesis of small-sized analogs of KNI-272. The smaller dipeptide analogs were synthesized and shown to have anti-HIV activity and good pharmacokinetic properties.3.Determination of anti-HIV activity of KNI compounds was carried out using ATH8 cell line, peripheral blood cells from AIDS patients, and AZT-insensitive cells.4.Pharmacokinetic analysis of KNI-272 in rats. Bioavailabilities were determined by oral and i.v. administration.5.Examination of animal scale-up. Pharmacokinetic profiles were simulated using parameters obtained from rats, rabbits and beagle dogs.6.Estimation of anti-HIV activity using HuPBMC-SCID mice as an HIV model. HIV was infected into severe combined immunodeficiency mice inoculated with human peripheral blood mononuclear cells and used for the study.7.Clinical study of KNI-272 in AIDS patients.8.Examination of interaction between KNI-272 and KNI-272-insensitive variant of HIV protease. Less