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Design, identification and development of novel antiviral agents active against HIV

设计、鉴定和开发新型抗艾滋病病毒药物

基本信息

批准号：
14207025
负责人：
MITSUYA Hiroaki
金额：
$ 27.21万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207025/
关键词：
HIV AIDS multi drug resistance reverse taranscriptase protease inhibitor CCR5 inhibitor 多剤耐性 Gaq ケモカイン CCR5 spirodiketopiperazine誘導体 LD78β

项目摘要

In this project, we identified several novel anti-HIV-agents active against multi-drug resistant HIV (HIV_<MDR>). UIC96003 is a novel PI that contains a unique bis-tetrahydrofuranyl-urethane and exerts potent activity against a wide spectrum of HIV_<MDR> strains (Yoshimura & Mitsuya, J.Virol. 76:1349-58,2002). UIC-96003's derivative, UIC94017/TMC114 (Koh & Mitsuya, AAC. 47:3123-29,2003), is now in Phase II clinical trials in the Europe. We also identified novel spirodiketopiperazine (SDP)-containing CCR5 inhibitors such as AK602/ON04128/GW873140, which exerted potent activity against R5-HIV. AK602 potently blocks HIV gp120 binding to CCR5 and suppresses HIV infection, but only moderately inhibits CC-chemokine RANTES binding to CCR5 (Maeda & Mitsuya, J.Virol. in press), in agreement with our observation that anti-HIV acitivity and the function of CC-chemokines are not always correlated (Miyakawa & Mitsuya, JBC. 277:4649-55,2002). AK602 has proved to have favorable pharmacokinetic profiles and now has been in Phase II clinical trial in the US.In the other area of research, we identified novel mechanisms of the emergence of resistance against existing reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). In particular, we demonstrated the pathways of the emergence of multi-NRTI-resistant HIV variants (Matsumi & Mitsuya, AIDS 17:1-11,2003) and reported that certain mutations in HIV's Gag are linked with high levels of viral resistance agianst multiple PIs (Gatanaga & Mitsuya, JBC. 277:5952-61,2002).

在这个项目中，我们发现了几种新的抗HIV药物(HIV_&lt；MDR&>t；)。UIC96003是一种新的PI，它含有独特的双四氢呋喃基氨基甲酸酯，并对广泛的HIV_&mdr&gt；株(Yoshimura&Mitsuya，J.Virol)具有强大的活性。76：1349-58,2002)。UIC-96003‘S衍生物，UIC94017/TMC114(Koh&Mitsuya，AAc.47：3123-29,2003)，目前正在欧洲进行第二阶段临床试验。我们还发现了新的含有螺二酮哌嗪(SDP)的CCR5抑制剂，如AK602/ON04128/GW873140，它们对R5-HIV具有很强的活性。AK602能有效地阻断HIV gp120与CCR5的结合并抑制HIV感染，但仅适度抑制CC趋化因子RANTES与CCR5的结合(Maeda&Mitsuya，J.Virol)。与我们的观察一致，即抗HIV活性和CC趋化因子的功能并不总是相关的(Miyakawa&Mitsuya，JBC。277：4649-55,2002)。AK602已被证明具有良好的药代动力学特征，目前已在美国进行第二阶段临床试验。在其他研究领域，我们发现了对现有逆转录酶抑制剂(RTI)和蛋白水解酶抑制剂(PI)产生耐药性的新机制。特别是，我们展示了多NRTI耐药艾滋病毒变异株的出现途径(MatSumi&Mitsuya，AIDS 17：1-11,2003)，并报告了艾滋病毒Gag的某些突变与对多重PI的高水平病毒耐药性有关(Gatanaga&Mitsuya，JBC)。277：5952-61,2002)。