1 Molpharm Lab, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway. firstname.lastname@example.org unknown4 Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet5 Molpharm Lab, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Organic and Biomolecular Chemistry, 2013, Vol 11, Issue 47, p. 8202-8