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

Zack G Zachariassen; Stefanie Thiele; Erik A Berg; Pernille Rasmussen; Torgils Fossen; Mette M Rosenkilde; Jon Våbenø; Bengt Erik Haug

doi:10.1016/j.bmc.2014.07.004

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

Bioorg Med Chem. 2014 Sep 1;22(17):4759-69. doi: 10.1016/j.bmc.2014.07.004. Epub 2014 Jul 14.

Authors

Zack G Zachariassen¹, Stefanie Thiele², Erik A Berg³, Pernille Rasmussen³, Torgils Fossen³, Mette M Rosenkilde², Jon Våbenø⁴, Bengt Erik Haug⁵

Affiliations

¹ Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway.
² Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
³ Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
⁴ Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway. Electronic address: [email protected].
⁵ Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway. Electronic address: [email protected].

PMID: 25082513
DOI: 10.1016/j.bmc.2014.07.004

Abstract

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.

Keywords: CXCR4 antagonist; Cyclopentapeptide; Peptidomimetic; Scaffold.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Conformation
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Receptors, CXCR4 / antagonists & inhibitors*
Receptors, CXCR4 / metabolism
Structure-Activity Relationship

Substances

CXCR4 protein, human
Peptides, Cyclic
Receptors, CXCR4