title: Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists.
abstract: The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-D-Tyr(5)-), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i) the distal aromatic ring of the 2-Nal(3) side chain is required in order to maintain high potency and (ii) replacement of D-Tyr(5) with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr(5) was only 13-fold less potent than 2, which means that the D-Tyr(5) side chain is dispensable. These findings were rationalized based on molecular docking, and the collective structure-activity data for the cyclopentapeptides suggest that appropriately designed Arg(2)-2-Nal(3) dipeptidomimetics have potential as CXCR4 antagonists.
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway. jon.vabeno@uit.no.
authors.forename: Jignesh
authors.initials: J
authors.lastname: Mungalpara
authors.forename: Zack G
authors.initials: ZG
authors.lastname: Zachariassen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: Jon
authors.initials: J
authors.lastname: Våbenø
mesh_terms: D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C527276:CXCR4 protein, human; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4