title: Anti-HIV activity and resistance profile of the CXC chemokine receptor 4 antagonist POL3026.
abstract: We have studied the mechanism of action of Arg(*)-Arg-Nal(2)-Cys(1x)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(1x)-Arg-Gly-(d-Pro)(*) (POL3026), a novel specific beta-hairpin mimetic CXC chemokine receptor (CXCR)4 antagonist. POL3026 specifically blocked the binding of anti-CXCR4 monoclonal antibody 12G5 and the intracellular Ca(2+) 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 (EC(50)) 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-1alpha-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.
authors.affiliation: Retrovirology Laboratory IrsiCaixa and AIDS Unit, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Moncunill
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugón
authors.forename: Imma
authors.initials: I
authors.lastname: Clotet-Codina
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pauls
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.forename: Anuska
authors.initials: A
authors.lastname: Llano
authors.forename: Barbara
authors.initials: B
authors.lastname: Romagnoli
authors.forename: Jan W
authors.initials: JW
authors.lastname: Vrijbloed
authors.forename: Frank O
authors.initials: FO
authors.lastname: Gombert
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Steve
authors.initials: S
authors.lastname: De Marco
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal; D001596:Benzylamines; D020013:Calcium Signaling / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D000080027:Cyclams; D024882:Drug Resistance, Viral / Q000187:drug effects*; D006678:HIV / Q000187:drug effects / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; C516700:POL3026 peptide; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; D014759:Viral Envelope Proteins; C088327:plerixafor