title: Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4).
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.
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway.
authors.forename: Zack G
authors.initials: ZG
authors.lastname: Zachariassen
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Thiele
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Berg
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Pernille
authors.initials: P
authors.lastname: Rasmussen
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Torgils
authors.initials: T
authors.lastname: Fossen
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway. Electronic address: jon.vabeno@uit.no.
authors.forename: Jon
authors.initials: J
authors.lastname: Våbenø
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway. Electronic address: Bengt-Erik.Haug@farm.uib.no.
authors.forename: Bengt Erik
authors.initials: BE
authors.lastname: Haug
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C527276:CXCR4 protein, human; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4
keywords: CXCR4 antagonist; Cyclopentapeptide; Peptidomimetic; Scaffold