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United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
2008
Link zum Volltext
Quelle
Electronic Journals Library
Beschreibungen/Notizen
We have studied the mechanism of action of Arg * -Arg-Nal 2 -Cys(1Ã)-Tyr-Gln-Lys-( d -Pro)-Pro-Tyr-Arg-Cit-Cys(1Ã)-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 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-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.