title: CCR5 pharmacology methodologies and associated applications.
abstract: The G protein-coupled chemokine (C-C motif) receptor, CCR5, was originally characterized as a protein responding functionally to a number of CC chemokines. As with chemokine receptors in general, studies indicate that CCR5 plays a role in inflammatory responses to infection, although its exact role in normal immune function is not completely defined. The vast majority of research into CCR5 has been focused on its role as an essential and predominant coreceptor for HIV-1 entry into host immune cells. Discovery of this role was prompted by the elucidation that individuals homozygous for a 32 bp deletion in the CCR5 gene do not express the receptor at the cell surface, and as a consequence, are remarkably resistant to HIV-1 infection, and apparently possess no other clear phenotype. Multiple studies followed with the ultimate aim of identifying drugs that functionally and physically blocked CCR5 to prevent HIV-1 entry, and thus provide a completely new approach to treating infection and AIDS, the world's biggest infectious disease killer. To this end, functional antagonists with potent anti-HIV-1 activity have been discovered, as best exemplified by maraviroc, the first new oral drug for the treatment of HIV-1 infection in 10 years. In this chapter, the specific methods used to characterize CCR5 primary pharmacology and apply the data generated to enable drug discovery, notably maraviroc, for the treatment of HIV infection and potentially inflammatory-based indications, are described.
authors.affiliation: Pfizer GRD-Sandwich Laboratories, Sandwich, Kent, United Kingdom.
authors.forename: Roy
authors.initials: R
authors.lastname: Mansfield
authors.forename: Sarah
authors.initials: S
authors.lastname: Able
authors.forename: Paul
authors.initials: P
authors.lastname: Griffin
authors.forename: Becky
authors.initials: B
authors.lastname: Irvine
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Malcolm
authors.initials: M
authors.lastname: Macartney
authors.forename: Ken
authors.initials: K
authors.lastname: Miller
authors.forename: James
authors.initials: J
authors.lastname: Mills
authors.forename: Carolyn
authors.initials: C
authors.lastname: Napier
authors.forename: Iva
authors.initials: I
authors.lastname: Navratilova
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.forename: Graham
authors.initials: G
authors.lastname: Rickett
authors.forename: Harriet
authors.initials: H
authors.lastname: Root
authors.forename: Elna
authors.initials: E
authors.lastname: van der Ryst
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Patrick
authors.initials: P
authors.lastname: Dorr
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000627:therapeutic use; D055808:Drug Discovery / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc