Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists
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Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists. / Mungalpara, Jignesh; Zachariassen, Zack G; Thiele, Stefanie; Rosenkilde, Mette M; Våbenø, Jon.
In: Organic & Biomolecular Chemistry, Vol. 11, No. 47, 21.12.2013, p. 8202-8.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 119829595