Joint study on protease-targeted anti-AIDS drugs

HIV编码一种病毒特异性天冬氨酸蛋白酶，该蛋白酶负责处理gag和gag-pol多蛋白，并负责逆转录病毒的增殖。HIV蛋白酶被认为是开发抗艾滋病药物的潜在靶点。基于底物过渡态模拟概念和ph - pro作为病毒特异性裂解序列，我们设计并合成了一类新的HIV蛋白酶抑制剂，该抑制剂含有非天然氨基酸allophenylnorstatine （Apns）作为羟基甲基羰基同分异构体。经先导优化研究，选择最优的三肽抑制剂kynostatin (KNI)-272作为候选药物进行药代动力学和临床研究。今年，我们为开发KNI-272作为抗hiv药物进行了以下研究1。前药KNI-272的制备及大规模合成。制备了一种通过分子内N-O酰基重排在体内转化为活性形式的水溶性前药。建立了一种高效、立体选择性的大规模合成KNI-272的药代动力学研究方法。KNI-272小型类似物的合成。合成了较小的二肽类似物，并显示出抗hiv活性和良好的药代动力学性质。利用ATH8细胞系、艾滋病患者外周血细胞和azt不敏感细胞检测KNI化合物的抗hiv活性。KNI-272在大鼠体内的药动学分析。通过口服和静脉给药测定生物利用度。动物放大检查。采用从大鼠、家兔和比格犬获得的参数模拟药代动力学特征。用hupmc - scid小鼠作为HIV模型的抗HIV活性评估。用人外周血单个核细胞接种严重联合免疫缺陷小鼠感染HIV，并用于研究。KNI-272在艾滋病患者中的临床研究。HIV蛋白酶KNI-272和KNI-272不敏感变体之间相互作用的检测。少

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