Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
J Virol ; 77(9): 5201-8, 2003 May.
Article in English | MEDLINE | ID: mdl-12692222

ABSTRACT

Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the consecutive interaction of the envelope glycoprotein gp120 with CD4 and a coreceptor such as CCR5 or CXCR4. The CCR5 coreceptor is used by the most commonly transmitted HIV-1 strains that often persist throughout the course of infection. Compounds targeting CCR5-mediated entry are a novel class of drugs being developed to treat HIV-1 infection. In this study, we have identified the mechanism of action of two inhibitors of CCR5 function, SCH-350581 (AD101) and SCH-351125 (SCH-C). AD101 is more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines. Both molecules also block the binding of several anti-CCR5 monoclonal antibodies that recognize epitopes in the second extracellular loop of CCR5. Alanine mutagenesis of the transmembrane domain of CCR5 suggests that AD101 and SCH-C bind to overlapping but nonidentical sites within a putative ligand-binding cavity formed by transmembrane helices 1, 2, 3, and 7. We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5.


Subject(s)
CCR5 Receptor Antagonists , Cyclic N-Oxides/pharmacology , HIV-1/drug effects , HIV-1/pathogenicity , Piperidines , Pyridines/pharmacology , Amino Acid Sequence , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , CD4-Positive T-Lymphocytes/virology , Cells, Cultured , HIV Envelope Protein gp120/metabolism , Humans , Membrane Fusion , Models, Molecular , Molecular Sequence Data , Oximes , Pyridines/chemistry , Receptors, CCR5/chemistry , Receptors, CCR5/genetics , Receptors, CCR5/metabolism , Virus Replication
SELECTION OF CITATIONS
SEARCH DETAIL
...