Backbone cyclic helix mimetic of chemokine (C–C motif) receptor 2: A rational approach for inhibiting dimerization of G protein-coupled receptors

• Published in: Bioorganic & medicinal chemistry 2013-07, Vol.21 (13), p.3958-3966
• Main Authors: Hurevich, Mattan, Ratner-Hurevich, Maya, Tal-Gan, Yftah, Shalev, Deborah E., Ben-Sasson, Shlomo Z., Gilon, Chaim
• Format: Article
• Language: English
• Subjects: Backbone cyclization; CC chemokine receptors; Cell Line; Chemotaxis - drug effects; G protein-coupled receptors; GPCR dimerization; Helix mimetics; Humans; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Multiple Sclerosis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Protein Multimerization - drug effects; Protein Structure, Secondary; Receptors, CCR2 - chemistry; Receptors, CCR2 - metabolism; Urea - chemistry; Urea - pharmacology; Urea cyclization
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.03.019

‘Helix walk’ enables helix mimetic of CCR2 dimerization region by urea backbone cyclization. The transmembrane helical bundle of G protein-coupled receptors (GPCRs) dimerize through helix–helix interactions in response to inflammatory stimulation. A strategy was developed to target the helical dimerization site of GPCRs by peptidomimetics with drug like properties. The concept was demonstrated by selecting a potent backbone cyclic helix mimetic from a library that derived from the dimerization region of chemokine (C–C motif) receptor 2 (CCR2) that is a key player in Multiple Sclerosis. We showed that CCR2 based backbone cyclic peptide having a stable helix structure inhibits specific CCR2-mediated chemotactic migration