Joint Study on AIDS Drug Based on HIV Protease

基于HIV蛋白酶的艾滋病药物联合研究

• 批准号: 08044325
• 负责人: KISO Yoshiaki
• 金额: $ 7.42万
• 依托单位: KYOTO PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08044325/
• 关键词: HIV Protease; Molecular Recognition; AIDS Therapeutics; Substrate Transition State; HIV Protease Inhibitor; Peptide Synthesis; Enzyme Inhibitor; Anti-HIV Activity

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.

基于HIV蛋白酶的底物过渡态概念，我们设计并合成了一种高选择性和强效的HIV蛋白酶抑制剂（kni272）。KNI-272具有较低的细胞毒性，能与HIV蛋白酶活性位点特异性相互作用，是根据HIV蛋白酶的反应机制合理设计的，有望成为一种理想的抗艾滋病药物。因此，从这些结果出发，分析KNI-272与HIV蛋白酶的相互作用表明，KNI-272具有受限构象，是一种理想的过渡态模拟物。此外，我们对突变型HIV蛋白酶进行了分子结构分析，并基于突变酶与抑制剂的相互作用，合理设计了一系列新的抗HIV药物。在突变型HIV和HIV-2中，它们的HIV蛋白酶具有较低的酶活性。此外，据报道，突变型HIV表现出低传染性，HIV-2具有低致病性。这些事实表明，低酶活性是低传染性的原因之一。从酶的化学结构水平对病毒致病性的分子机制进行分析。因此，我们发现了小尺寸的二肽HIV蛋白酶抑制剂KNI-413和KNI-549。此外，我们设计了具有抗HIV-1活性的KNI-241和较小的KNI-727，它们对KNI-272具有抗性。本研究在对酶与抑制剂复合物进行结构分析的基础上，合理开展了HIV蛋白酶抑制剂的研究，旨在为控制HIV的耐药性建立方法学。

项目成果

Yasushi Ohno: "Solution conformations of KNI-272,a tripeptide HIV protease inhibitor designed on the basis of substrate transition state : Determined by NMRspectroscopy and simulated annealing calculations." Bioorg.Med.Chem.4・9. 1565-1572 (1996)

Yasushi Ohno：“基于底物过渡态设计的三肽 HIV 蛋白酶抑制剂 KNI-272 的溶液构象：通过 NMR 光谱和模拟退火计算确定。”1565-1572（1996）。

Yun-Xing Wang: "Solution NMR Evidence That the HIV-1 Protease Catalytic Aspartyl Groups Have Different Ionization States in the Complex Formed with Asymmetric Drug KNI-272." Biochemistry. 35・31. 9945-9950 (1996)

王运兴：“HIV-1 蛋白酶催化天冬氨酰基团在不对称药物 KNI-272 形成的复合物中具有不同电离状态的溶液 NMR 证据”35・31 (1996)。

Toshiyuki Goto: "Inhibition sites in HIV-infected cells by a protease inhibitor,KNI-272." AIDS Res.Newsletter. 153 (1997)

Toshiyuki Goto：“蛋白酶抑制剂 KNI-272 在 HIV 感染细胞中的抑制位点。”

Y.Ohno, Y.Kiso, and Y.Kobayashi: "Solution conformations of KNI-272, a tripeptide HIV protease inhibitor designed on the basis of substrate transition state : Determined by NMR spectroscopy and simulated annealing calculations." Bioorg.Med.Chem.4 (9). 156

Y.Ohno、Y.Kiso 和 Y.Kobayashi：“基于底物过渡态设计的三肽 HIV 蛋白酶抑制剂 KNI-272 的溶液构象：通过 NMR 光谱和模拟退火计算确定。”

Yoshiaki Kiso: "Design synthesis of substrate-based peptidomimetic HIV protease inhibitors containing the hydroxymethylcarbonyl isostere." Biopolymers. 40・2. 235-244 (1996)

Yoshiaki Kiso：“基于底物的拟肽 HIV 蛋白酶抑制剂的设计合成，含有羟甲基羰基等排物”40・2（1996）。