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Studies of novel small molecule anti-HIV-1 agents targeting the chemokine receptor CCR5

针对趋化因子受体 CCR5 的新型小分子抗 HIV-1 药物的研究

基本信息

批准号：
15390174
负责人：
BABA Masanori
金额：
$ 7.36万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390174/
关键词：
AIDS HIV-1 Chemotherapy Chemokine receptor CCR5 Oral bioavailability

项目摘要

In 1999, we have reported TAK-779 as a novel CCR5 antagonist with highly potent and selective inhibition of R5 HIV-1 replication in cell cultures. However, TAK-779 has poor oral bioavailability, and its development was discontinued by an unfavorable effect on injection sites. Our continuous efforts to find effective and orally bioavailable CCR5 antagonists have recently identified TAK-220 and TAK-652 through chemical modification of lead compounds discovered by a high throughput screening. The chemical structures of TAK-220 and TAK-652 are completely different each other. TAK-220 specifically inhibited ligand binding to CCR5 at nanomolar concentrations, whereas it did not inhibit ligand binding to other chemokine receptors. On the other hand, TAK-652 inhibited ligand binding to CCR2b as well as CCR5 at a similar concentration. Both compounds could inhibit CCR5-using HIV-1 replication including various clinical isolates at nanomolar concentrations, yet they did not show any inhibition of CXCR4-using HIV-1 replication. Furthermore, recombinant CCR5-using viruses carrying different subtype envelope proteins were found to be equally susceptible to these compounds. Single oral administration of TAK-652 up to 100 mg was safe and well-tolerated in humans. TAK-652 may be able to retain the plasma concentration sufficiently higher than the target concentration by once daily administration at a reasonable dose. Thus, TAK-652 has proved to be a promising therapeutic agent for HIV-1 infection, and the evaluation for its clinical efficacy in HIV-1-infected individuals appears to be worth conducting.

1999年，我们报道了一种新的CCR5拮抗剂TAK-779，它对细胞培养中的R5HIV-1复制具有高效和选择性的抑制作用。然而，TAK-779的口服生物利用度较差，其开发因注射部位的不利影响而中断。我们不断努力寻找有效的口服生物利用CCR5拮抗剂，最近通过高通量筛选发现的先导化合物的化学修饰鉴定了TAK-220和TAK-652。TAK-220和TAK-652的化学结构完全不同。Tak-220在纳摩尔浓度下特异性地抑制配体与CCR5的结合，而不抑制配体与其他趋化因子受体的结合。另一方面，TAK-652在相似浓度下抑制与CCR2b和CCR5的配体结合。这两个化合物在纳摩尔浓度下都能抑制包括各种临床分离株在内的使用HIV-1的CCR5复制，但它们对使用HIV-1的CXCR4复制没有任何抑制作用。此外，携带不同亚型包膜蛋白的重组CCR5病毒被发现对这些化合物同样敏感。单次口服高达100毫克的TAK-652在人类中是安全和耐受性良好的。合理剂量的Tak-652每日给药一次，可使血药浓度维持在足够高于靶浓度的水平。因此，TAK-652已被证明是一种很有前途的HIV-1感染治疗剂，对HIV-1感染者的临床疗效评估似乎是值得进行的。