Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function
Autor: | Jim A. Turpin, J. J. Oppenheim, Michael Grimm, William G. Rice, Christopher J. Michejda, Robert Blumenthal, Nadya I. Tarasova, O. M. Z. Howard, Thomas Korte |
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Rok vydání: | 1998 |
Předmět: |
CD4-Positive T-Lymphocytes
CCR2 Anti-HIV Agents Chemokine receptor CCR5 Immunology Virus Replication Membrane Fusion Cell Line Chemokine receptor Naphthalenesulfonates Humans Immunology and Allergy CCL13 biology Cell Biology Cell biology CXCL2 Chemokine binding Biochemistry HIV-1 biology.protein XCL2 Receptors Chemokine Chemokines HeLa Cells CCL21 |
Zdroj: | Journal of Leukocyte Biology. 64:6-13 |
ISSN: | 1938-3673 0741-5400 |
DOI: | 10.1002/jlb.64.1.6 |
Popis: | The intersection of the HIV and the chemokine fields began with the observation that HIV entry into cells could be blocked by certain chemokines. Subsequent work showed that HIV entry is dependent on the presence of specific chemokine receptors. These observations led us to evaluate a series of compounds, ureido analogs of distamycin previously reported to block HIV entry into cells in vitro, for chemokine antagonist activity. One of the distamycin analogs, 2,2′[4,4′-[[aminocarbonyl]amino]bis[N,4′-di[pyrrole-2-carboxamide-1,1′-dimethyl]]-6,8 napthalenedisulfonic acid] hexasodium salt (NSC 651016), is shown here to inhibit syncytia formation and cell fusion. Mechanistic studies showed that this inhibition was not due to conformational changes in gp120-gp41 induced by target cell CD4 and chemokine co-receptor and was therefore not due to interference with binding of HIV-1. Additional mechanistic studies demonstrated that NSC 651016 inhibited chemokine binding to specific chemokine receptors, induced CXCR4 and CCR5 receptor internalization, and inhibited chemokine-induced chemotaxis by macrophage inflammatory protein (MIP)-1α, MIP-1β, RANTES, and stromal-derived factor-1α but not monocyte chemotactic protein-1. Thus, we describe a novel compound that inhibits in vivo replication of HIV-1 by down-regulation of co-receptors. These data lead us to propose that NSC 651016 may have in vivo anti-inflammatory activity. J. Leukoc. Biol. 64: 6–13; 1998. |
Databáze: | OpenAIRE |
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