Study on strategy for AIDS drugs against mutant viruses

基于HIV蛋白酶的底物过渡态概念，我们设计并合成了含有羟甲基羰基（HMC）同分异构体的HIV蛋白酶抑制剂。其中，三肽衍生物KNI-272具有高选择性、强抑制HIV蛋白酶和高体内抗病毒活性。核磁共振和分子模拟研究表明，HMC基团与HIV蛋白酶活性位点有良好的相互作用，HMC同工异构体是一种理想的过渡态模拟物。目前用于治疗的HIV蛋白酶抑制剂剂量大，副作用多。此外，HIV蛋白酶抑制剂诱导HIV-1蛋白酶的氨基酸序列突变和敏感性降低，尽管HIV蛋白酶抑制剂被认为是低突变诱导剂，因为它们攻击酶活性中心。因此，我们开始设计和合成低分子量HIV蛋白酶抑制剂。小而有效的抑制剂在成本、耐药诱导、药代动力学和给药剂量方面可能是有利的。考虑到这些因素，基于酶和抑制剂之间的分子识别，我们设计了含有HMC异构体的小型高效HIV蛋白酶抑制剂，并找到了克服耐药和副作用的可能性。此外，我们还合成了含有逆转录酶抑制剂的二肽HIV蛋白酶抑制剂的前药型偶联物。我们发现这些新型抗hiv药物具有良好的细胞膜渗透性和协同作用，并提出了“双药”概念。

Based on the substrate transition state concept of HIV protease, we have designed and synthesized HIV protease inhibitors containing hydroxymethylcarbony (HMC) isostere. Among them, a tripeptide derivative KNI-272 exhibited high selectivity, potent HIV protease inhibition, and high in vivo antiviral activity. NMR and molecular modeling studies showed that the HMC group interacts favorable with HIV protease active site and that the HMC isostere is an ideal transition state mimic.The HIV protease inhibitors currently used for therapeutics need high dose and thus cause various side effects. Furthermore, HIV protease inhibitors induce mutation in the amino acid sequence of HIV-1 protease and decreased sensitivity, although HIV protease inhibitors have been considered as low mutation inducer because they attack the enzyme active center.Therefore, we started the design and synthesis of low molecular weight HIV protease inhibitors. The small and potent inhibitors may be favorable in terms of the cost, resistance induction, pharmacokinetics and administration dose.Taking into consideration of these factors, based on the molecular recognition between the enzyme and inhibitors, we designed small-sized highly-potent HIV protease inhibitors containing HMC isostere, and found the possibility to overcome the resistance and side effects. Furthermore, we synthesized prodrug-type conjugates of dipeptide HIV protease inhibitors with a reverse transcriptase inhibitors. We found that these new type of anti-HIV drugs showed excellent cell membrane permeability and synergistic effect, and proposed "Double-Drug" concept.