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• W2147410318 endingPage "1273" @default.
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• W2147410318 abstract "We have studied the mechanism of action of Arg^*-Arg-Nal²-Cys(1×)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(1×)-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-1α-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." @default.
• W2147410318 created "2016-06-24" @default.
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• W2147410318 date "2008-01-08" @default.
• W2147410318 modified "2023-10-18" @default.
• W2147410318 title "Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026" @default.
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• W2147410318 doi "https://doi.org/10.1124/mol.107.042911" @default.
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