Engineering and screening the N-terminus of chemokines for drug discovery

Chevigné, Andy; Fiévez, Virginie; Schmit, Jean-Claude; Deroo, Sabrina

doi:10.1016/j.bcp.2011.07.091

Cited by 24 publications

(23 citation statements)

References 209 publications

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“…It is well established that the N terminus of chemokines is required for optimal binding and signaling through specific G protein-coupled receptors (42). The conformational change induced in the N terminus of CCL3 following Evasin-1 binding was therefore suggested to be important in explaining the inhibition (23).…”

Section: Discussionmentioning

confidence: 99%

Identification of the Pharmacophore of the CC Chemokine-binding Proteins Evasin-1 and -4 Using Phage Display

Bonvin

Dunn

Rousseau

et al. 2014

Journal of Biological Chemistry

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Background:The selectivity profiles of the closely related chemokine-binding proteins Evasin-1 and -4 differ. Results: Using phage display, we identified the N-terminal region of Evasin-4 as key for the interaction with CC chemokines. Conclusion: Evasin-1 and -4 use different domains for target binding. Significance: Phage display allowed rapid insight into their different selectivities, which could aid rational design of inhibitory proteins.

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Section: Discussionmentioning

confidence: 99%

Identification of the Pharmacophore of the CC Chemokine-binding Proteins Evasin-1 and -4 Using Phage Display

Bonvin

Dunn

Rousseau

et al. 2014

Journal of Biological Chemistry

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“…Preclinical therapeutic appoaches include small molecule inhibitors or neutralizing antibodies and modified chemokines (Chevigne et al 2011). For example, a broad spectrum inhibitor of CC and CXC chemokines, NR58-3.14.3, a retroinversoanalogue of a 12-mer peptide, reduces the inflammatory response and the lesion size and, consequently, improves neurological function in a rat model of cerebral ischaemia (Beech et al 2001).…”

Section: Neuroinflammationmentioning

confidence: 99%

Chemokines in CNS injury and repair

2012

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Recruitment of inflammatory cells is known to drive the secondary damage cascades that are common to injuries of the central nervous system (CNS). Cell activation and infiltration to the injury site is orchestrated by changes in the expression of chemokines, the chemoattractive cytokines. Reducing the numbers of recruited inflammatory cells by the blocking of the action of chemokines has turned out be a promising approach to diminish neuroinflammation and to improve tissue preservation and neovascularization. In addition, several chemokines have been shown to be essential for stem/progenitor cell attraction, their survival, differentiation and cytokine production. Thus, chemokines might indirectly participate in remyelination, neovascularization and neuroprotection, which are important prerequisites for CNS repair after trauma. Moreover, CXCL12 promotes neurite outgrowth in the presence of growth inhibitory CNS myelin and enhances axonal sprouting after spinal cord injury (SCI). Here, we review current knowledge about the exciting functions of chemokines in CNS trauma, including SCI, traumatic brain injury and stroke. We identify common principles of chemokine action and discuss the potentials and challenges of therapeutic interventions with chemokines.

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“…Early chemokine structure-function studies showed that truncation of the chemokine N-terminus transforms chemokine agonists into antagonists [20, 76, 77]. Recent studies of the CCL5 N-terminus demonstrate that extension of the chemokine N-terminus produces variant-specific functional outcomes, such as receptor internalization, degradation, recycling, or biased signaling [54, 77]. Similar approaches have since been applied to other chemokines [77].…”

Section: Beyond Sitementioning

confidence: 99%

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

Kleist

Getschman

Ziarek

et al. 2016

Biochemical Pharmacology

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114

113

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Chemokine receptor (CKR) signaling forms the basis of essential immune cellular functions, and dysregulated CKR signaling underpins numerous disease processes of the immune system and beyond. CKRs, which belong to the seven transmembrane domain receptor (7TMR) superfamily, initiate signaling upon binding of endogenous, secreted chemokine ligands. Chemokine-CKR interactions are traditionally described by a two-step/two-site mechanism, in which the CKR N-terminus recognizes the chemokine globular core (i.e. site 1 interaction), followed by activation when the unstructured chemokine N-terminus is inserted into the receptor TM bundle (i.e. site 2 interaction). Several recent studies challenge the structural independence of sites 1 and 2 by demonstrating physical and allosteric links between these supposedly separate sites. Others contest the functional independence of these sites, identifying nuanced roles for site 1 and other interactions in CKR activation. These developments emerge within a rapidly changing landscape in which CKR signaling is influenced by receptor PTMs, chemokine and CKR dimerization, and endogenous non-chemokine ligands. Simultaneous advances in the structural and functional characterization of 7TMR biased signaling have altered how we understand promiscuous chemokine-CKR interactions. In this review, we explore new paradigms in CKR signal transduction by considering studies that depict a more intricate architecture governing the consequences of chemokine-CKR interactions.

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Engineering and screening the N-terminus of chemokines for drug discovery

Cited by 24 publications

References 209 publications

Identification of the Pharmacophore of the CC Chemokine-binding Proteins Evasin-1 and -4 Using Phage Display

Identification of the Pharmacophore of the CC Chemokine-binding Proteins Evasin-1 and -4 Using Phage Display

Chemokines in CNS injury and repair

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

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