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

1999年，我们报告了TAK-779作为一种新型CCR 5拮抗剂，对细胞培养物中的R5 HIV-1复制具有高度强效和选择性抑制作用。然而，TAK-779的口服生物利用度较差，并且由于对注射部位的不利影响而停止开发。我们不断努力寻找有效的口服生物可利用的CCR 5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抑制配体与CCR 5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在相似浓度下抑制配体与CCR 2b以及CCR 5的结合。这两种化合物在纳摩尔浓度下都能抑制使用CCR 5的HIV-1复制，包括各种临床分离株，但它们对使用CXCR 4的HIV-1复制没有任何抑制作用。此外，发现携带不同亚型包膜蛋白的重组CCR 5使用病毒对这些化合物同样敏感。人体单次口服高达100 mg的TAK-652是安全且耐受性良好的。通过以合理剂量每日一次给药，TAK-652可能能够保持血浆浓度充分高于目标浓度。因此，TAK-652已被证明是一种有前景的HIV-1感染治疗药物，其在HIV-1感染个体中的临床疗效评价似乎值得进行。

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.