RT Journal Article
SR Electronic
T1 The Relative Activity of “Function Sparing” HIV-1 Entry Inhibitors on Viral Entry and CCR5 Internalization: Is Allosteric Functional Selectivity a Valuable Therapeutic Property?
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 490
OP 501
DO 10.1124/mol.108.052555
VO 75
IS 3
A1 Vanessa M. Muniz-Medina
A1 Stacey Jones
A1 Jodi M. Maglich
A1 Cristin Galardi
A1 Robert E. Hollingsworth
A1 Wieslaw M. Kazmierski
A1 Robert G. Ferris
A1 Mark P. Edelstein
A1 Karen E. Chiswell
A1 Terry P. Kenakin
YR 2009
UL http://molpharm.aspetjournals.org/content/75/3/490.abstract
AB 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:-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. The American Society for Pharmacology and Experimental Therapeutics