Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

TY - JOUR

T1 - Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

AU - Zachariassen, Zack G

AU - Thiele, Stefanie

AU - Berg, Erik A

AU - Rasmussen, Pernille

AU - Fossen, Torgils

AU - Rosenkilde, Mette M

AU - Våbenø, Jon

AU - Haug, Bengt Erik

N1 - Copyright © 2014 Elsevier Ltd. All rights reserved.

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Structure-activity relationship studies of the cyclopentapeptide CXCR4 antagonists (cyclo(-l-/d-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-d-Tyr(5)-)) suggest that the l-/d-Arg(1)-Arg(2)-2-Nal(3) tripeptide sequence contained within these cyclopentapeptides serves as a recognition motif for peptidic CXCR4 antagonists. Starting by dissecting the cyclopentapeptide structure and reintroducing cyclic constraints in a stepwise manner, we here report a novel class of scaffold-based tripeptidomimetic CXCR4 antagonists based on the d-Arg-Arg-2-Nal motif. Biological testing of the prototype compounds showed that they represent new peptidomimetic hits; importantly, the modular nature of the scaffold provides an interesting starting point for future ligand optimization.

AB - Structure-activity relationship studies of the cyclopentapeptide CXCR4 antagonists (cyclo(-l-/d-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-d-Tyr(5)-)) suggest that the l-/d-Arg(1)-Arg(2)-2-Nal(3) tripeptide sequence contained within these cyclopentapeptides serves as a recognition motif for peptidic CXCR4 antagonists. Starting by dissecting the cyclopentapeptide structure and reintroducing cyclic constraints in a stepwise manner, we here report a novel class of scaffold-based tripeptidomimetic CXCR4 antagonists based on the d-Arg-Arg-2-Nal motif. Biological testing of the prototype compounds showed that they represent new peptidomimetic hits; importantly, the modular nature of the scaffold provides an interesting starting point for future ligand optimization.

KW - Dose-Response Relationship, Drug

KW - Drug Design

KW - Humans

KW - Molecular Conformation

KW - Peptides, Cyclic

KW - Receptors, CXCR4

KW - Structure-Activity Relationship

U2 - 10.1016/j.bmc.2014.07.004

DO - 10.1016/j.bmc.2014.07.004

M3 - Journal article

C2 - 25082513

SN - 0968-0896

VL - 22

SP - 4759

EP - 4769

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 17

ER -