Molecular design of HIV protease inhibitors restricted to active conformation

HIV蛋白酶抑制剂的分子设计仅限于活性构象

• 批准号: 09557203
• 负责人: KISO Yoshiaki
• 金额: $ 8.13万
• 依托单位: KYOTO PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557203/
• 关键词: HIV protease; Molecular Recognition; AIDS Therapeutics; Substrate Transition State; HIV Protease Inhibitor; Peptide Synthesis; Enzyme Inhibitor; Anti-HIV Activity; ペプチドミメティック; ドラッグデザイン; 薬剤耐性; 酵素・阻害剤複合体; 抗ウイルス薬

Introduction of HIV protease inhibitors with new action mechanism as anti-HIV drugs provided a new development in the combination therapy of AIDS. However, there are many problems to be solved such as dose, economics, side effects, resistance, transport to central nervous system.In order to overcome these problems, we designed and synthesized small-sized HIV protease inhibitors containing hydroxymethlcarbonyl (HHMC) isostere, and ideal transition state mimic, based on the data obtained from NMR structural analysis and molecular modeling studies. Inhibitors of small size and high potency are advantageous in terms of cost, and resistance induction as well, because molecular recognition studies showed that these inhibitors interacts with the enzyme at fewer sites. Furthermore, smaller-sized inhibitors may exhibit better tissue transportation, improved pharmacokinetics and may be usable at lower dose. These results indicate that HMC-containing depicted inhibitors are promising for combination therapy as HIV protease inhibitors of next generation.O-N Acyl migration-type prodrug of HIV protease inhibitors exhibited better solubility and improved bioavailability, which shows excellent cell membrane permeability and synergistic effect acting on the different targets in HIV replication by intracellularly generated components. This new hybrid type drugs are expected as a new type of resistance surmountable anti-AIDS agents.

具有新作用机制的HIV蛋白酶抑制剂作为抗HIV药物的出现，为艾滋病的综合治疗提供了新的发展方向。为了克服这些问题，我们在NMR结构分析和分子模拟研究的基础上，设计合成了含有羟甲基羰基（HHMC）等排体和理想过渡态模拟物的小分子HIV蛋白酶抑制剂。小尺寸和高效力的抑制剂在成本和抗性诱导方面是有利的，因为分子识别研究表明这些抑制剂在较少的位点与酶相互作用。此外，较小尺寸的抑制剂可以表现出更好的组织运输，改善的药代动力学，并且可以以较低剂量使用。O-N酰基迁移型HIV蛋白酶抑制剂前体药物具有较好的溶解性和生物利用度，表现出良好的细胞膜渗透性和细胞内生成组分协同作用于HIV复制过程中不同靶点的协同效应。这种新型的杂交型药物有望成为一种新型的耐药性可克服的抗艾滋病药物。

项目成果

木曽 良明: "廣川有機薬化学実験講座第1巻-創薬指向の分子設計:第5章HIVプロテアーゼ阻害剤"廣川書店. 245 (2000)

木曾义明：“广川有机药物化学实验课程第 1 卷 - 药物发现的分子设计：第 5 章 HIV 蛋白酶抑制剂”广川书店 245 (2000)。

Tsutomu Mimoto, Ryohei Kato, Haruo Takaku, Satoshi Nojima, Keisuke Terashima, Satoru Misawa, Tominaga Fukazawa, Takamasa Ueno, Hideharu Sato, Makoto Shintani, Yoshiaki Kiso, and Hideya Hayashi: "Structure-activity relationship of small-sized HIV protease

Tsutomu Mimoto、Ryohei Kato、Haruo Takaku、Satoshi Nojima、Keisuke Terashima、Satoru Misawa、Tominaga Fukazawa、Takamasa Ueno、Hideharu Sato、Makoto Shintani、Yoshiaki Kiso 和 Hideya Hayashi：“小型 HIV 蛋白酶的结构-活性关系

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Yoshiaki Kiso：“共价连接的 HIV-1 蛋白酶二聚体类似物和肽模拟抑制剂的设计和合成。”J.Synthetic Org.Chem.56·11（1998）。

Tooru Kimura: "A new class of anti-HIV agents : synthesis and activity of conjugates of HIV protease inhibitors with a reverse transcriptase inhibitor." Bioorg.Med.Chem.Lett.9・6. 803-806 (1999)

Tooru Kimura：“一类新的抗 HIV 药物：HIV 蛋白酶抑制剂与逆转录酶抑制剂的缀合物的合成和活性。”Bioorg.Med.Chem.Lett.9·6（1999）。

Yoshio Hayashi: "Structure-activity relationship studies of chloromethyl ketone derivatives for selective human chymase inhibitors."Bioorg.Med.Chem.Lett.. 10・3. 199-201 (2000)

Yoshio Hayashi：“用于选择性人食糜酶抑制剂的氯甲基酮衍生物的结构-活性关系研究”。Bioorg.Med.Chem.Lett.10・3（2000）。