Study on strategy for AIDS drugs against mutant viruses

艾滋病药物针对突变病毒的策略研究

• 批准号: 10044327
• 负责人: KISO Yoshiaki
• 金额: $ 6.53万
• 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 (A).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10044327/
• 关键词: HIV protease inhibitor; Molecular Recognition; AIDS Therapeutics; Substrate Transition State; Double Drug; Peptide Synthesis; Enzyme Inhibitor; Anti-HIV Activity; ペプチドミメティック; 抗ウイルス薬; ドラッグデザイン; 薬剤耐性; 酵素・阻害剤複合体

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.

基于HIV蛋白酶底物过渡态的概念，我们设计并合成了含羟甲基羰基（HMC）等排体的HIV蛋白酶抑制剂。其中，三肽衍生物KNI-272表现出高选择性、有效的HIV蛋白酶抑制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蛋白酶活性中心有良好的相互作用，HMC电子等排体是一种理想的过渡态模拟物。此外，尽管HIV蛋白酶抑制剂由于攻击酶的活性中心而被认为是低突变诱导剂，但HIV蛋白酶抑制剂会诱导HIV-1蛋白酶的氨基酸序列发生突变并降低敏感性，因此我们开始了低分子量HIV蛋白酶抑制剂的设计和合成。考虑到小分子强效抑制剂在成本、耐药诱导、药代动力学和给药剂量等方面的优势，我们基于酶与抑制剂的分子识别，设计了含HMC等排体的小分子高效HIV蛋白酶抑制剂，为克服耐药和毒副作用提供了可能。此外，我们合成了二肽HIV蛋白酶抑制剂与逆转录酶抑制剂的前药型缀合物。我们发现这些新型抗HIV药物具有良好的细胞膜通透性和协同作用，并提出了“双药”概念。

项目成果

Yoshiaki Kiso: "Design and synthesis of a covalently linked HIV-1 protease dimer analog and peptidomimetic inhibitors." J.Synthetic Org.Chem.56・11. 896-907 (1998)

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）。

Yoshiaki Kiso: "Synthesis of HIV protease analogs and inhibitors." Proc.7th Akabori Conf. : Jpn.-Ger.Symp.Peptide Chemistry. 46-49 (1998)

Yoshiaki Kiso：“HIV 蛋白酶类似物和抑制剂的合成。”

Etsuko Kato: "Determination of the Rate of Monomer Interchange in a Ligand-Bound Homodimeric Protein from NOESY Cross Peaks : Application to the HIV Protease/KNI-529 Complex"J. Amer. Chem. Soc.. 121・11. 2607-2608 (1999)

加藤悦子：“从 NOESY 交叉峰测定配体结合的同源二聚体蛋白中的单体交换率：在 HIV 蛋白酶/KNI-529 复合物中的应用”J. Soc. 121・11。 (1999)

Yoshiaki Kiso: "Small Dipeptide-Based HIV Protease Inhibitors Containing the Hydroxymethylcarbonyl Isostere as an ideal Transition-State Mimic."Biopolymers. 51・1. 59-68 (1999)

Yoshiaki Kiso：“含有羟甲基羰基电子等排物的小二肽 HIV 蛋白酶抑制剂作为理想的过渡态模拟物”。生物聚合物 51・1 (1999)。

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 i

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 i