Identification of a Potent, Selective Non-peptide CXCR2 Antagonist That Inhibits Interleukin-8-induced Neutrophil Migration

White, John R.; Lee, Judithann M.; Young, Peter R.; Hertzberg, Robert; Jurewicz, Anthony J.; Chaikin, Margery A.; Widdowson, Katherine L.; Foley, James J.; Martin, Lenox D.; Griswold, Don E.; Sarau, Henry M.

doi:10.1074/jbc.273.17.10095

Cited by 385 publications

(310 citation statements)

References 38 publications

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“…Small molecule inhibitors of CCR1 and CXCR2 are known, but their binding sites are not (45,46). There may be both generality and specificity to how small molecule inhibitors interact with CCchemokine receptors, exemplified by TAK-779.…”

Section: Discussionmentioning

confidence: 99%

A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5

Dragic

Trkola²,

Thompson³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

415

370

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HIV-1 entry into CD4 ؉ cells requires the sequential interactions of the viral envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors CCR5 and CXCR4. A plausible approach to blocking this process is to use small molecule antagonists of coreceptor function. One such inhibitor has been described for CCR5: the TAK-779 molecule. To facilitate the further development of entry inhibitors as antiviral drugs, we have explored how TAK-779 acts to prevent HIV-1 infection, and we have mapped its site of interaction with CCR5. We find that TAK-779 inhibits HIV-1 replication at the membrane fusion stage by blocking the interaction of the viral surface glycoprotein gp120 with CCR5. We could identify no amino acid substitutions within the extracellular domain of CCR5 that affected the antiviral action of TAK-779. However, alanine scanning mutagenesis of the transmembrane domains revealed that the binding site for TAK-779 on CCR5 is located near the extracellular surface of the receptor, within a cavity formed between transmembrane helices 1, 2, 3, and 7.

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Section: Discussionmentioning

confidence: 99%

A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5

Dragic

Trkola²,

Thompson³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

415

370

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“…The minor colocalization of endocytosed F protein with lamp-1 further supported the idea that only a small amount of the protein is transported to the late endosomal/lysosomal compartment. As proteins that are recycled to the cell surface and proteins that are targeted to lysosomes have similar sorting signals, it must be assumed that the relative position of the signal within the NiV F cytoplasmic tail mediates internalization and recycling rather than lysosomal targeting (27,28).…”

Section: Discussionmentioning

confidence: 99%

The Nipah Virus Fusion Protein Is Cleaved within the Endosomal Compartment

Diederich

Moll

Klenk

et al. 2005

Journal of Biological Chemistry

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Nipah virus (NiV) is a recently emerged and highly pathogenic paramyxovirus that causes a systemic infection in animals and humans and can infect a wide range of cultured cells. Interestingly, the NiV fusion (F) protein has a single arginine at the cleavage site similar to paramyxoviruses that are activated by exogenous trypsin-like enzymes only present in specific cells and tissues and therefore only cause localized infections. We show here that NiV F activation is not mediated by an exogenous serum protease but by an endogenous ubiquitous cellular protease after endocytosis of the protein.In addition to endocytosis, acidification of the endosome is a prerequisite for F cleavage. These results show that activation of the NiV F protein depends on a type of proteolytic cleavage that is clearly different from what is known for other paramyxoviral and orthomyxoviral fusion proteins. To our knowledge, this is the first example of a viral class I fusion protein whose activation depends on clathrin-mediated constitutive endocytosis.

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“…It has been shown to compete with 125 I-human IL-8 for binding to human recombinant CXCR2 (expressed on Chinese hamster ovary cell membranes) with an IC 50 of 9.3 Ϯ 0.8 nM (n ϭ 7), while its affinity for human recombinant CXCR1 is three orders of magnitude lower (IC 50 ϭ 9, 633 Ϯ 892 nM (n ϭ 3)) (methods described in Ref. 42). The selectivity of the compound for human CXCR2 is further supported by its failure to compete for ligand-binding to other human chemokine receptors, including CXCR3, CXCR4, CCR2, CCR7, CCR8, and CX3CR1, as well as its lack of activity in 66 additional receptor binding and enzyme assays previously described (43).…”

Section: Statistical Analysesmentioning

confidence: 99%

A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

Podolin

Bolognese

Foley

et al. 2002

The Journal of Immunology

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146

112

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Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits 125I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC50 = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC50 = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-α, IL-8, PGE2, leukotriene B4, and leukotriene C4 levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-α and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC50 = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.

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Identification of a Potent, Selective Non-peptide CXCR2 Antagonist That Inhibits Interleukin-8-induced Neutrophil Migration

Abstract: Interleukin-8 (IL-8The present findings suggest that CXCR2 is responsible for neutrophil chemotaxis and margination induced by IL-8. This selective antagonist will be a useful tool compound to define the role of CXCR2 in inflammatory diseases where neutrophils play a major role.

Cited by 385 publications

References 38 publications

A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5

A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5

The Nipah Virus Fusion Protein Is Cleaved within the Endosomal Compartment

A Potent and Selective Nonpeptide Antagonist of CXCR2 Inhibits Acute and Chronic Models of Arthritis in the Rabbit

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