Rational Designing of CXCR-4 Agonists and Antagonists: Synthesis of Novel Cyclam Derivatives of Stromal Cell-Derived Factor (SDF-1)

Abstract

Stromal cell-derived factor (SDF-1) is a primordial chemokine of the CXC subfamily and has multiple biological activities on a variety of cell types [1]. SDF-1 is of unique interest because it is the only chemokine that regulates the cycling of both long-term culture initiating and primitive erythroid and granulopoietic colony-forming cells [2]. The N-terminus of SDF-1 is a critical site for CXCR4 receptor binding and activation [3]. We describe here new, active, truncated analogues of SDF-1 [4]. These peptides have the N-terminal region (residues 1–14) linked to the C-terminal (residues 55–67) α-helix. A four-glycine linker approximates the distance between these C-terminal and N-terminal regions in the native folded SDF-1. In this study some of these 31-residue analogues are cyclized by lactamization between residues K20–E24 or residues E24–K28. All of these analogues showed enhanced in vitrobiological activity, especially the cyclized ones.