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First published on January 8, 2008; DOI: 10.1124/mol.107.042911

0026-895X/08/7304-1264-1273$20.00
Mol Pharmacol 73:1264-1273, 2008

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Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026Formula

Gemma Moncunill, Mercedes Armand-Ugón, Imma Clotet-Codina, Eduardo Pauls, Ester Ballana, Anuska Llano, Barbara Romagnoli, Jan W. Vrijbloed, Frank O. Gombert, Bonaventura Clotet, Steve De Marco, and José A. Esté

Retrovirology Laboratory IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain (G.M., M.A.-U., I.C.-C., E.P., E.B., A.L., B.C., J.A.E.); and Polyphor Ltd., Allschwil, Switzerland (B.R., J.W.V., F.O.G., S.D.M.)

We have studied the mechanism of action of Arg*-Arg-Nal2-Cys(1x)-Tyr-Gln-Lys-(D-Pro)-Pro-Tyr-Arg-Cit-Cys(1x)-Arg-Gly-(D-Pro)* (POL3026), a novel specific β-hairpin mimetic CXC chemokine receptor (CXCR)4 antagonist. POL3026 specifically blocked the binding of anti-CXCR4 monoclonal antibody 12G5 and the intracellular Ca2+ signal induced by CXC chemokine ligand 12. POL3026 consistently blocked the replication of human immunodeficiency virus (HIV), including a wide panel of X4 and dualtropic strains and subtypes in several culture models, with 50% effective concentrations (EC50) at the subnanomolar range, making POL3026 the most potent CXCR4 antagonist described to date. However, 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100)-resistant and stromal cell-derived factor-1{alpha}-resistant HIV-1 strains were cross-resistant to POL3026. Time of addition experiments and a multiparametric evaluation of HIV envelope function in the presence of test compounds confirmed the activity of POL3026 at an early step of virus replication: interaction with the coreceptor. Generation of HIV-1 resistance to POL3026 led to the selection of viruses 12- and 25-fold less sensitive and with mutations in gp120, including the V3 loop region. However, POL3026 prevented the emergence of CXCR4-using variants from an R5 HIV-1 strain that may occur in the presence of anti-HIV agents targeting CC chemokine receptor 5.

Received October 25, 2007; accepted December 27, 2007

Address correspondence to: Dr. José A. Esté, Retrovirology Laboratory IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. E-mail: jaeste{at}irsicaixa.es






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