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Compound class: Peptide or derivative
Comment: This is a small peptide that mimics the glycosaminoglycan (GAG) binding domain found in the C-terminal α helix of the CXCL8 cytokine . It competes with CXCL8 for binding to GAGs, and by interfering in this interaction, reduces CXCL8-mediated inflammatory responses (leukocyte activation and extravasation to inflammatory sites).
The archetypal GAG-binding motif on CXC chemokines takes the form XBBBXXBX (where B = a basic amino acid and X = any nonbasic amino acid) .
The reference article also describes small peptides that interfere with CCL5 and CXCL12γ GAG binding .
Chemokine interactions with GAGs localise the chemokines around cell surfaces and the extracellular matrix. This provides a guidance mechanism for leukocyte migration . Disrupting this guidance mechanism is predicted to produce anti-inflammatory effects, by reducing the ability of pro-inflammatory cells to migrate to sites of inflammation in response to cytokine signals.
1. Falsone A, Wabitsch V, Geretti E, Potzinger H, Gerlza T, Robinson J, Adage T, Teixeira MM, Kungl AJ. (2013)
Designing CXCL8-based decoy proteins with strong anti-inflammatory activity in vivo.
Biosci. Rep., 33 (5). [PMID:23919527]
2. McNaughton EF, Eustace AD, King S, Sessions RB, Kay A, Farris M, Broadbridge R, Kehoe O, Kungl AJ, Middleton J. (2018)
Novel Anti-Inflammatory Peptides Based on Chemokine-Glycosaminoglycan Interactions Reduce Leukocyte Migration and Disease Severity in a Model of Rheumatoid Arthritis.
J. Immunol., 200 (9): 3201-3217. [PMID:29572348]
3. Proudfoot AE, Fritchley S, Borlat F, Shaw JP, Vilbois F, Zwahlen C, Trkola A, Marchant D, Clapham PR, Wells TN. (2001)
The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity.
J. Biol. Chem., 276 (14): 10620-6. [PMID:11116158]
4. Proudfoot AEI, Johnson Z, Bonvin P, Handel TM. (2017)
Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System.
Pharmaceuticals (Basel), 10 (3). [PMID:28792472]