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ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2‐dependent migration
Author(s) -
Auvynet Constance,
Chanville Camille Baudesson,
Hermand Patricia,
Dorgham Karim,
Piesse Christophe,
Pouchy Charlotte,
Carlier Ludovic,
Poupel Lucie,
Barthélémy Sandrine,
Felouzis Virginie,
Lacombe Claire,
Sagan Sandrine,
Chemtob Sylvain,
Quiniou Christiane,
Salomon Benoit,
Deterre Philippe,
Sennlaub Florian,
Combadière Christophe
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201500116
Subject(s) - ccr2 , allosteric regulation , chemistry , pharmacology , chemotaxis , chemokine receptor , in vivo , chemokine , experimental autoimmune encephalomyelitis , biochemistry , receptor , microbiology and biotechnology , biology , inflammation , immunology , genetics
CC chemokine receptor type 2 (CCR2) is a key molecule in inflammatory diseases and is an obvious drug target for the treatment of inflammation. A number of nonpeptidic, competitive CCR2 antagonists have been developed, but none has yet been approved for clinical use. Our aim was to identify a short peptide that showed allosteric antagonism against human and mouse CCR2. On the basis of sequence analysis and 3‐dimensional modeling, we identified an original 7‐ d ‐amino acid peptidic CCR2 inhibitor that we have called extracellular loop 1 inverso (ECL1i), d(LGTFLKC). In vitro , ECL1i selectively and potently inhibits CC chemokine ligand type 2 (CCL2)‐triggered chemotaxis (IC 50 , 2 μM) but no other conventional CCL2‐associated events. We used the classic competitive CCR2 antagonist, BMS22 {2‐[(isopropylaminocarbonyl)amino]‐ N ‐[2‐[[cis‐2‐[[4‐(methylthio)benzoyl] amino]cyclohexyl]amino]‐2‐oxoethyl]‐5‐(trifluoromethyl)benzamide}, as positive control and inhibited CCL2‐dependent chemotaxis with an IC 50 of 18 nM. As negative control, we used a peptide with the same composition as ECL1i, but in a different sequence, d(FKLTLCG). In vivo , ECL1i (4 mg/kg) interfered with CCR2‐positive cell recruitment and attenuated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This study establishes ECL1i as the first allosteric inhibitor of CCR2 with functional selectivity. ECL1i is a promising new agent in therapeutic development, and it may, by its selective effect, increase our understanding of CCR2 signaling pathways and functions.—Auvynet, C., Baudesson de Chanville, C., Hermand, P., Dorgham, K., Piesse, C., Pouchy, C., Carlier, L., Poupel, L., Barthélémy, S., Felouzis, V., Lacombe, C., Sagan, S., Chemtob, S., Quiniou, C., Salomon, B., Deterre, P., Sennlaub, F., Combadière, C. ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2‐dependent migration. FASEB J. 30, 2370–2381 (2016). www.fasebj.org