scholarly journals A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

1997 ◽  
Vol 186 (8) ◽  
pp. 1395-1400 ◽  
Author(s):  
Benjamin J. Doranz ◽  
Kathie Grovit-Ferbas ◽  
Matthew P. Sharron ◽  
Si-Hua Mao ◽  
Matthew Bidwell Goetz ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Viral Entry ◽  
Small Molecule Inhibitor ◽  
Chemokine Receptor Cxcr4 ◽  
Mechanism Of Inhibition ◽  
Molecule Inhibitor ◽  
Immunodeficiency Virus ◽  
Hiv 1

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell– tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1α–mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

scholarly journals Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function

1998 ◽  
Vol 64 (1) ◽  
pp. 6-13 ◽  
Author(s):  
O. M. Z. Howard ◽  
Thomas Korte ◽  
Nadya I. Tarasova ◽  
Michael Grimm ◽  
Jim A. Turpin ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

2005 ◽  
Vol 7 (5) ◽  
pp. 493-500 ◽  
Author(s):  
Alan Lau ◽  
Karra M. Swinbank ◽  
Parvin S. Ahmed ◽  
Debra L. Taylor ◽  
Stephen P. Jackson ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Atm Kinase ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals Regulation of Human Immunodeficiency Virus Type 1 Infection, β-Chemokine Production, and CCR5 Expression in CD40L-Stimulated Macrophages: Immune Control of Viral Entry

2001 ◽  
Vol 75 (9) ◽  
pp. 4308-4320 ◽  
Author(s):  
Robin L. Cotter ◽  
Jialin Zheng ◽  
Myhanh Che ◽  
Douglas Niemann ◽  
Ying Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Chemokine Receptor ◽  
Viral Entry ◽  
Chemokine Production ◽  
Tnf Α ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Mononuclear phagocytes (MP) and T lymphocytes play a pivotal role in the host immune response to human immunodeficiency virus type 1 (HIV-1) infection. Regulation of such immune responses can be mediated, in part, through the interaction of the T-lymphocyte-expressed molecule CD40 ligand (CD40L) with its receptor on MP, CD40. Upregulation of CD40L on CD4+ peripheral blood mononuclear cells during advanced HIV-1 disease has previously been reported. Based on this observation, we studied the influence of CD40L-CD40 interactions on MP effector function and viral regulation in vitro. We monitored productive viral infection, cytokine and β-chemokine production, and β-chemokine receptor expression in monocyte-derived macrophages (MDM) after treatment with soluble CD40L. Beginning 1 day after infection and continuing at 3-day intervals, treatment with CD40L inhibited productive HIV-1 infection in MDM in a dose-dependent manner. A concomitant and marked upregulation of β-chemokines (macrophage inhibitory proteins 1α and 1β and RANTES [regulated upon activation normal T-cell expressed and secreted]) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) was observed in HIV-1-infected and CD40L-treated MDM relative to either infected or activated MDM alone. The addition of antibodies to RANTES or TNF-α led to a partial reversal of the CD40L-mediated inhibition of HIV-1 infection. Surface expression of CD4 and the β-chemokine receptor CCR5 was reduced on MDM in response to treatment with CD40L. In addition, treatment of CCR5- and CD4-transfected 293T cells with secretory products from CD40L-stimulated MDM prior to infection with a CCR5-tropic HIV-1 reporter virus led to inhibition of viral entry. In conclusion, we demonstrate that CD40L-mediated inhibition of viral entry coincides with a broad range of MDM immune effector responses and the down-modulation of CCR5 and CD4 expression.

Identification of a Novel Small Molecule Inhibitor that Targets HIV-1 Envelope Maturation

2007 ◽  
Vol 74 (3) ◽  
pp. A27-A27
Author(s):  
J JIMENEZ ◽  
J CAO ◽  
L JACKSON ◽  
Q PENG ◽  
H WU ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals Biochemical and Genetic Characterizations of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions

2003 ◽  
Vol 77 (19) ◽  
pp. 10528-10536 ◽  
Author(s):  
Qi Guo ◽  
Hsu-Tso Ho ◽  
Ira Dicker ◽  
Li Fan ◽  
Nannan Zhou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Small Molecule ◽  
Viral Entry ◽  
Binding Pocket ◽  
Gp120 Protein ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.

A small-molecule inhibitor of HIV-1 Rev function detected by a diversity screen based on RRE-Rev interference

2018 ◽  
Vol 156 ◽  
pp. 68-77 ◽  
Author(s):  
Silvia Prado ◽  
Manuela Beltrán ◽  
Ángela Moreno ◽  
Luis M. Bedoya ◽  
José Alcamí ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor

1998 ◽  
Vol 4 (1) ◽  
pp. 72-77 ◽  
Author(s):  
George A. Donzella ◽  
Dominique Schols ◽  
Steven W. Lin ◽  
José A. Esté ◽  
Kirsten A. Nagashima ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Hiv 1

scholarly journals Inhibitory Effects of Small-Molecule CCR5 Antagonists on Human Immunodeficiency Virus Type 1 Envelope-Mediated Membrane Fusion and Viral Replication

2001 ◽  
Vol 45 (12) ◽  
pp. 3538-3543 ◽  
Author(s):  
Katsunori Takashima ◽  
Hiroshi Miyake ◽  
Rika A. Furuta ◽  
Jun-Ichi Fujisawa ◽  
Yuji Iizawa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Membrane Fusion ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Small Molecule ◽  
Inhibitory Effects ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed β-d-galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC50s) for membrane fusion and viral replication were 0.87 ± 0.11 and 1.4 ± 0.1 nM, respectively. These values corresponded well to the IC50 for 125I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC50s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors.

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