title: The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property?
abstract: Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1 [CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection ( Science 307: 1434-1440, 2005 ). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance, although TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.
authors.affiliation: Infectious Diseases Discovery Performance Unit, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Muniz-Medina
authors.forename: Stacey
authors.initials: S
authors.lastname: Jones
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Maglich
authors.forename: Cristin
authors.initials: C
authors.lastname: Galardi
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hollingsworth
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ferris
authors.forename: Mark P
authors.initials: MP
authors.lastname: Edelstein
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chiswell
authors.forename: Terry P
authors.initials: TP
authors.lastname: Kenakin
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5