Synthetic Agonists for the CXCR4 Receptor: SAR, Signaling Pathways and Peptidomimetic Transition

CXCR4 a G-protein coupled receptor is an important pharmaceutical target in a variety of diseases including HIV and many forms of cancer. CXCR4 is therefore an important pharmaceutical target but besides the cognate agonist SDF-1 only synthetic antagonists/inverse agonists are targeting CXCR4 with pertinent affinities. CXCR4 has important household functions; those antagonists lead to the emergence of significant adverse drug effects. We recently describe nanomolar CXCR4 agonists [1] where the SDF-1 N-terminus was grafting to the inverse agonist T140 [2] (Figure 1). In order to translate these peptidic compounds into peptidomimetic agonists, permitting eventual pharmaceutical applications, the present contribution describes the SAR of the grafted SDF-N-terminus in order to pinpoint the agonist-antagonist transition and to determine the peptidomimetic transition strategies.