Structural Determinants of Gi Activation by Peptidic CXCR4 Agonists

摘要

Therapeutic intervention targeting the CXCR4/CXCL12 axis is a tricky endeavor, considering their many intricate physiological roles. This receptor is vastly expressed in the majority of tissues, and is of great importance in multiple essential processes, such as hematopoiesis and angiogenesis. The use of CXCR4 antagonists is limited by the numerous adverse effects, such as cardiotoxicity [1]. The elaboration of CXCR4 agonists is therefore highly interesting for potential treatment options. Our team has elaborated synthetic CXCR4 agonists [2] by combining the TV-terminus of the endogenous ligand, CXCL12, with a high affinity inverse agonist of CXCR4, T140 [3], to produce high affinity agonists. These compounds have subsequently proven efficacious for both in vitro and in vivo CXCR4-mediated chemotaxis. Signaling assays have shown that none of these agonists induce beta-arrestin-2 recruitment. Previous assessment of the affinities of the compounds showed improvement by lengthening of the chain to up to 10 amino acids, and that correct positioning of the chain on the T140 scaffold was essential. The present study aims to evaluate if the main CXCR4 signaling pathway, Got;, is activated by the compounds, and establish which of their structural elements are associated with higher Goij response.