The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property? - PubMed (original) (raw)
Comparative Study
. 2009 Mar;75(3):490-501.
doi: 10.1124/mol.108.052555. Epub 2008 Dec 8.
Affiliations
- PMID: 19064629
- DOI: 10.1124/mol.108.052555
Comparative Study
The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property?
Vanessa M Muniz-Medina et al. Mol Pharmacol. 2009 Mar.
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.
Similar articles
- Chemokine (C-C motif) receptor 5-using envelopes predominate in dual/mixed-tropic HIV from the plasma of drug-naive individuals.
Irlbeck DM, Amrine-Madsen H, Kitrinos KM, Labranche CC, Demarest JF. Irlbeck DM, et al. AIDS. 2008 Jul 31;22(12):1425-31. doi: 10.1097/QAD.0b013e32830184ba. AIDS. 2008. PMID: 18614865 - Identification and characterization of INCB9471, an allosteric noncompetitive small-molecule antagonist of C-C chemokine receptor 5 with potent inhibitory activity against monocyte migration and HIV-1 infection.
Shin N, Solomon K, Zhou N, Wang KH, Garlapati V, Thomas B, Li Y, Covington M, Baribaud F, Erickson-Viitanen S, Czerniak P, Contel N, Liu P, Burn T, Hollis G, Yeleswaram S, Vaddi K, Xue CB, Metcalf B, Friedman S, Scherle P, Newton R. Shin N, et al. J Pharmacol Exp Ther. 2011 Jul;338(1):228-39. doi: 10.1124/jpet.111.179531. Epub 2011 Apr 1. J Pharmacol Exp Ther. 2011. PMID: 21459966 - HIV entry: new insights and implications for patient management.
Hughes A, Nelson M. Hughes A, et al. Curr Opin Infect Dis. 2009 Feb;22(1):35-42. doi: 10.1097/QCO.0b013e3283213093. Curr Opin Infect Dis. 2009. PMID: 19532079 Review. - HIV-1 entry inhibition by small-molecule CCR5 antagonists: a combined molecular modeling and mutant study using a high-throughput assay.
Labrecque J, Metz M, Lau G, Darkes MC, Wong RS, Bogucki D, Carpenter B, Chen G, Li T, Nan S, Schols D, Bridger GJ, Fricker SP, Skerlj RT. Labrecque J, et al. Virology. 2011 May 10;413(2):231-43. doi: 10.1016/j.virol.2011.02.016. Epub 2011 Mar 9. Virology. 2011. PMID: 21388649 - HIV type 1 tropism and inhibitors of viral entry: clinical implications.
Weber J, Piontkivska H, Quiñones-Mateu ME. Weber J, et al. AIDS Rev. 2006 Apr-Jun;8(2):60-77. AIDS Rev. 2006. PMID: 16848274 Review.
Cited by
- Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition.
Kenakin T. Kenakin T. Nat Rev Drug Discov. 2024 Aug;23(8):626-644. doi: 10.1038/s41573-024-00958-9. Epub 2024 Jun 18. Nat Rev Drug Discov. 2024. PMID: 38890494 Review. - G protein-coupled receptors: structure- and function-based drug discovery.
Yang D, Zhou Q, Labroska V, Qin S, Darbalaei S, Wu Y, Yuliantie E, Xie L, Tao H, Cheng J, Liu Q, Zhao S, Shui W, Jiang Y, Wang MW. Yang D, et al. Signal Transduct Target Ther. 2021 Jan 8;6(1):7. doi: 10.1038/s41392-020-00435-w. Signal Transduct Target Ther. 2021. PMID: 33414387 Free PMC article. Review. - Molecular binding mode of PF-232798, a clinical anti-HIV candidate, at chemokine receptor CCR5.
Zhu Y, Zhao YL, Li J, Liu H, Zhao Q, Wu BL, Yang ZL. Zhu Y, et al. Acta Pharmacol Sin. 2019 Apr;40(4):563-568. doi: 10.1038/s41401-018-0054-2. Epub 2018 Jun 25. Acta Pharmacol Sin. 2019. PMID: 29941870 Free PMC article. - Distinct Signaling Patterns of Allosteric Antagonism at the P2Y1 Receptor.
Gao ZG, Jacobson KA. Gao ZG, et al. Mol Pharmacol. 2017 Nov;92(5):613-626. doi: 10.1124/mol.117.109660. Epub 2017 Sep 1. Mol Pharmacol. 2017. PMID: 28864555 Free PMC article. - What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?
Kufareva I, Gustavsson M, Zheng Y, Stephens BS, Handel TM. Kufareva I, et al. Annu Rev Biophys. 2017 May 22;46:175-198. doi: 10.1146/annurev-biophys-051013-022942. Annu Rev Biophys. 2017. PMID: 28532213 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous