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，负责加工gag和gag-pol多蛋白以及逆转录病毒的增殖。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的概念，以Phe-Pro为病毒特异性切割序列，设计合成了一类新的含非天然氨基酸的HIV蛋白酶抑制剂--别苯去甲甲他汀（allopenylnorstatine，Apns），通过先导优化研究，得到了最优的三肽抑制剂，犬抑素（kynostatin，KNI）-272作为候选药物进行药代动力学和临床研究。本年度，我们为开发KNI-272作为抗HIV药物进行了以下研究：1. KNI-272前药的制备和大规模合成。制备了一种水溶性前药，其在体内通过分子内N-O酰基重排转化为活性形式。一种高效的 ...更多信息 建立了KNI-272的立体选择性大规模合成方法，并进行了药动学研究。2. KNI-272小分子类似物的合成。3.用ATH 8细胞、AIDS患者外周血细胞和AZT不敏感细胞对KNI-272的抗HIV活性进行了测定。4. KNI-272在大鼠体内的药代动力学分析。通过口服和静脉给药测定生物利用度。5.动物放大试验。使用从大鼠、兔和比格犬获得的参数模拟药代动力学曲线。6.使用HuPBMC-SCID小鼠作为HIV模型估计抗HIV活性。将HIV感染到接种人外周血单个核细胞的严重联合免疫缺陷小鼠中并用于研究。7. KNI-272在AIDS患者中的临床研究。8.检测KNI-272与HIV蛋白酶的KNI-272不敏感变体之间的相互作用。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