A novel CXCR4 antagonist for hematopoietic stem cell mobilization
ABSTRACT Hematopoietic stem cell (HSC) transplantation is a treatment option for hematological malignancies. Current mobilization regimes frequently result in inadequate numbers of HSC for transplant therefore alternative methods of mobilization are required.
The chemokine receptor CXCR4 and ligand SDF-1 are integrally involved in HSC homing and mobilization. Disruption of the SDF-1/CXCR4 axis by the CXCR4 anatagonist, plerixafor, is shown to improve HSC mobilization.
The molecular and in vivo pharmacology of plerixafor and subsequent clinical development is reviewed.
Preclinical studies demonstrate that plerixafor is a selective antagonist of CXCR4 and can rapidly mobilize HSC. Clinical trials demonstrated improved HSC mobilization when plerixafor was included in the mobilization regimen. These data suggest the potential for a significant role for plerixafor in hematological disease.
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- "A number of approaches for manipulation of chemokine biology are currently undergoing investigation (7), including small-molecule-specific chemokine receptor antagonists (8), virus-derived chemokine-binding proteins (9), and nonsignaling mutant chemokine “cell-jammers” (10). In each case, these strategies are specific for the blockade of single ligands or receptors. "
ABSTRACT: Interaction between chemokines and heparan sulfate (HS) is essential for leukocyte recruitment during inflammation. Previous studies have shown that a non-HS-binding mutant form of the inflammatory chemokine CCL7 can block inflammation produced by wild-type chemokines. This study examined the anti-inflammatory mechanism of a non-HS-binding mutant of the homeostatic chemokine CXCL12. Initial experiments demonstrated that mutant CXCL12 was an effective CXCR4 agonist. However, this mutant chemokine failed to promote transendothelial migration in vitro and inhibited the haptotactic response to wild-type CCL7, CXCL12, and CXCL8, and naturally occurring chemoattractants in synovial fluid from the rheumatoid synovium, including CCL2, CCL7, and CXCL8. Notably, intravenous administration of mutant CXCL12 also inhibited the recruitment of leukocytes to murine air pouches filled with wild-type CXCL12. Following intravenous administration, wild-type CXCL12 was cleared from the circulation rapidly, while the mutant chemokine persisted for >24 h. Chronic exposure to mutant CXCL12 in the circulation reduced leukocyte-surface expression of CXCR4, reduced the chemotactic response of these cells to CXCL12, and inhibited normal chemokine-mediated induction of adhesion between the alpha4beta1 integrin, VLA-4, and VCAM-1. These data demonstrate that systemic administration of non-HS-binding variants of CXCL12 can mediate a powerful anti-inflammatory effect through chemokine receptor desensitization.The FASEB Journal 09/2009; 23(11):3906-16. DOI:10.1096/fj.09-134643 · 5.48 Impact Factor
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ABSTRACT: Low temperature performance of a 150 W, 50 kHz, 24/48 V boost PWM dc-to-dc converter is reported. The efficiency of the converter using a molypermalloy powder (MPP) core based inductor went up from 94% at room temperature (23 C) to 95.9% at liquid nitrogen temperature (-196 C). A BSCCO based high temperature superconducting (HTS) inductor with a transition temperature of approximately -158 C was compared to a MPP core based inductor in terms of the power converter performance at liquid nitrogen temperature. The use of the HTS inductor in the converter tested yielded no significant performance improvement over the same converter with the MPP inductor. The experimental results are discussed along with the HTS inductor characteristics.
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ABSTRACT: Considering as a lead molecule the chemokine CXCR4 receptor antagonist AMD-3100, which shows significant anti-HIV activity in vitro and in vivo, we investigated a series of structurally related macrocyclic polyamines incorporating o,o'-phenanthroline or 2,2'-bipyridyl scaffolds as potential antiviral agents with lower toxicity and increased activity against both wild type X4-tropic and dual tropic HIV strains. The antiviral activity of these compounds was evaluated by susceptibility assays in PBMC (Peripheral Blood Mononuclear Cells) and compared to that of AMD-3100. The newly investigated compounds showed IC(50)s values in the low micromolar range and significantly inhibited the viral replication of wild type X4-tropic isolate and dual tropic strains. These macrocyclic polyamines constitute a promising class of HIV entry inhibitors.Molecules 02/2009; 14(5):1927-37. DOI:10.3390/molecules14051927 · 2.42 Impact Factor