Allosteric Modulation of Chemoattractant Receptors

Allegretti, Marcello; Cesta, Maria Candida; Locati, Massimo

doi:10.3389/fimmu.2016.00170

Cited by 22 publications

(29 citation statements)

References 65 publications

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“…In addition, NK cells ex vivo engineered to express chemokine receptors by gene transfer or by trogocytosis are under investigation for their better tissue homing and function ( 97 – 101 ). Conversely, a number of new clinical trials for immune-mediated diseases based on the use of chemokine receptor antagonists are ongoing and will help to understand the therapeutic potential of these important targets for NK cell-promoted pathologies ( 102 ). Finally, the emerging role of chemoattractant receptor interplay in the regulation of immune cell response may also lead to the discovery of molecules able to block chemokine receptor cross-inhibition thus allowing to unleash the full chemotactic potential of important NK cell receptors, such as CXCR4.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of Chemokine/Chemokine Receptor Axes and NK Cell Tissue Localization during Diseases

et al. 2016

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Chemokines are small chemotactic molecules that play key roles in physiological and pathological conditions. Upon signaling via their specific receptors, chemokines regulate tissue mobilization and trafficking of a wide array of immune cells, including natural killer (NK) cells. Current research is focused on analyzing changes in chemokine/chemokine receptor expression during various diseases to interfere with pathological trafficking of cells or to recruit selected cell types to specific tissues. NK cells are a heterogeneous lymphocyte population comprising several subsets endowed with distinct functional properties and mainly representing distinct stages of a linear development process. Because of their different functional potential, the type of subset that accumulates in a tissue drives the final outcome of NK cell-regulated immune response, leading to either protection or pathology. Correspondingly, chemokine receptors, including CXCR4, CXCR3, and CX3CR1, are differentially expressed by NK cell subsets, and their expression levels can be modulated during NK cell activation. At first, this review will summarize the current knowledge on the contribution of chemokines to the localization and generation of NK cell subsets in homeostasis. How an inappropriate chemotactic response can lead to pathology and how chemokine targeting can therapeutically affect tissue recruitment/localization of distinct NK cell subsets will also be discussed.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of Chemokine/Chemokine Receptor Axes and NK Cell Tissue Localization during Diseases

et al. 2016

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“…From a structural point of view an allosteric modulator may bind to a distinct receptor domain outside or close to the orthosteric binding site, a binding that secondarily promotes or reduces binding and/or the functional outcome mediated by a ligand that occupies the orthosteric binding site of the modulated receptor . The allosteric concept is likely to be applicable also to neutrophil GPCRs, and accordingly, novel allosteric inhibitors of the C5a receptor and the IL8 receptors CXCR1/2 have recently been described and entered clinical trials …”

Section: Introductionmentioning

confidence: 99%

Neutrophil priming that turns natural FFA2R agonists into potent activators of the superoxide generating NADPH-oxidase

Mårtensson

Holdfeldt

Sundqvist

et al. 2018

Journal of Leukocyte Biology

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Acetate, an agonist for the free fatty acid receptor 2 (FFA2R/GPR43), triggers an increase in the cytosolic concentration of free Ca in neutrophils without any assembly of the superoxide generating NADPH-oxidase. We show that the phenylacetamide compound 58 (Cmp 58; (S)-2-(4-chlorophenyl)-3,3-dimethyl-N-(5-phenylthiazol-2-yl)butanamide), lacking a direct activating effect on neutrophils, acts as a positive FFA2R modulator that turns acetate into a potent activating agonist that triggers an assembly of the NADPH-oxidase. The NADPH-oxidase activity could be further increased in neutrophils treated with the pro-inflammatory cytokine TNF-α. Many neutrophil chemoattractant receptors are stored in secretory organelles but no FFA2R mobilization was induced in neutrophils treated with TNF-α. The receptor selectivity was demonstrated through the inhibition of the neutrophil response induced by the combined action of acetate and Cmp 58 by the FFA2R antagonist CATPB. Receptor modulators that positively co-operate with natural FFA2R agonists and prime neutrophils in their response to such agonists, may serve as good tools for further unraveling the physiological functions of FFA2R and its involvement in various diseases. In this study, we show that neutrophils primed with a presumed allosteric FFA2R modulator produce increased amounts of reactive oxygen species when activated by receptor specific agonists.

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“…CXCR1 and CXCR2 are largely expressed on T lymphocytes and natural killer cells, playing a key role in acute and chronic inflammatory conditions. 235 Reparixin ( 163 ) is a noncompetitive NAM for CXCR1 (Figure 23) presenting a 400-fold higher efficacy in inhibiting CXCR1 activity versus CXCR2. 243 Compound 163 inhibits the signaling triggered by chemokine CXC ligand 8 (CXCL8) and binds CXCR1 at an allosteric site between TM I, III, and VI and has been advanced into a phase III clinical trial for pancreatic islet autotransplantaion.…”

Section: Recent Advances In the Discovery And Design Of Class A Gpcr mentioning

confidence: 99%

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

Wold

Chen²,

Cunningham³

et al. 2018

J. Med. Chem.

119

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G-protein-coupled receptors (GPCRs) have been tractable drug targets for decades with over one-third of currently marketed drugs targeting GPCRs. Of these, the class A GPCR superfamily is highly represented, and continued drug discovery for this family of receptors may provide novel therapeutics for a vast range of diseases. GPCR allosteric modulation is an innovative targeting approach that broadens the available small molecule toolbox and is proving to be a viable drug discovery strategy, as evidenced by recent FDA approvals and clinical trials. Numerous class A GPCR allosteric modulators have been discovered recently, and emerging trends such as the availability of GPCR crystal structures, diverse functional assays, and structure-based computational approaches are improving optimization and development. This Perspective provides an update on allosterically targeted class A GPCRs and their disease indications and the medicinal chemistry approaches toward novel allosteric modulators and highlights emerging trends and opportunities in the field.

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Allosteric Modulation of Chemoattractant Receptors

Cited by 22 publications

References 65 publications

Dysregulation of Chemokine/Chemokine Receptor Axes and NK Cell Tissue Localization during Diseases

Dysregulation of Chemokine/Chemokine Receptor Axes and NK Cell Tissue Localization during Diseases

Neutrophil priming that turns natural FFA2R agonists into potent activators of the superoxide generating NADPH-oxidase

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

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