title: CCR5 inhibitors: emergence, success, and challenges.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Cancer Institute, Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, Bethesda 20892, MD, USA. maedak@mail.nih.gov
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Debananda
authors.initials: D
authors.lastname: Das
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Nakata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D065100:CCR5 Receptor Antagonists; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D000077592:Maraviroc; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc