TY - JOUR

T1 - Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

AU - Mungalpara, Jignesh

AU - Zachariassen, Zack G

AU - Thiele, Stefanie

AU - Rosenkilde, Mette M

AU - Våbenø, Jon

PY - 2013/12/21

Y1 - 2013/12/21

N2 - 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.

AB - 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.

KW - Humans

KW - Models, Molecular

KW - Molecular Conformation

KW - Peptides, Cyclic

KW - Receptors, CXCR4

KW - Structure-Activity Relationship

U2 - 10.1039/c3ob41941j

DO - 10.1039/c3ob41941j

M3 - Journal article

C2 - 24150741

VL - 11

SP - 8202

EP - 8208

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

SN - 1470-4358

IS - 47

ER -