National Cancer Institute, Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Bethesda 20892, MD, USA.
Expert Opin Emerg Drugs. 2012 Jun;17(2):135-45. doi: 10.1517/14728214.2012.673584. Epub 2012 Apr 25.
The discovery of CC-chemokine receptor 5 (CCR5) as a human immunodeficiency virus type 1 (HIV-1) coreceptor opened a new avenue to exploit CCR5 as a potential target for the intervention of HIV-1's cellular entry.
Various small-molecule CCR5 inhibitors were identified in the last decade; however, maraviroc (MVC) is the only CCR5 inhibitor currently used in the clinic. Concerns and challenges that exist for wider clinical use of CCR5 inhibitors are discussed.
Although MVC-containing regimens have been recommended for treatment-naïve patients, MVC appears to have been used as one of drugs for salvage therapy rather than for treating drug-naïve patients. This is apparently due to MVC's twice-daily dosing schedule. Another significant disadvantage is that a costly tropism assay must be performed prior to MVC treatment. The access to inexpensive, sensitive, and rapid tropism tests should be made easily available. Only a few novel CCR5 inhibitors are presently in the pipeline. Development of potent and metabolically-stable novel CCR5 inhibitors allowing once-daily dosing regimens is needed. Development of CXCR4 inhibitors should greatly improve the treatment options available to patients infected with X4- and/or dual-tropic HIV-1 strains in combination with a CCR5 inhibitor.
发现 C 型趋化因子受体 5（CCR5）是人类免疫缺陷病毒 1 型（HIV-1）的辅助受体，为利用 CCR5 作为 HIV-1 细胞进入的潜在靶点开辟了新途径。
在过去十年中，已经鉴定出各种小分子 CCR5 抑制剂；然而，马拉维若（MVC）是目前临床应用的唯一 CCR5 抑制剂。讨论了广泛临床应用 CCR5 抑制剂存在的问题和挑战。
尽管含有 MVC 的方案已被推荐用于治疗初治患者，但 MVC 似乎已被用作挽救治疗的药物之一，而不是用于治疗初治患者。这显然是由于 MVC 的每日两次给药方案。另一个显著的缺点是，在 MVC 治疗之前必须进行昂贵的趋化性测定。应该更容易获得廉价、敏感和快速的趋化性检测。目前只有少数新型 CCR5 抑制剂处于研发阶段。需要开发具有强大和代谢稳定的新型 CCR5 抑制剂，允许每日一次给药方案。开发 CXCR4 抑制剂将极大地改善对感染 X4-和/或双嗜性 HIV-1 株的患者的治疗选择，与 CCR5 抑制剂联合使用。
