Agonists for the Chemokine Receptor CXCR4

作者：Lefrancois Marilou; Lefebvre Marie Reine; Saint Onge Genevieve; Boulais Philip E; Lamothe Simon; Leduc Richard; Lavigne Pierre; Heveker Nikolaus; Escher Emanuel^*

来源：ACS Medicinal Chemistry Letters, 2011, 2(8): 597-602.

DOI：10.1021/ml200084n

• CXCR4
• agonist
• CXCL12
• T140
• chemotaxis

The development of agonists for the chemokine receptor CXCR4 could provide promising therapeutic candidates. On the basis of previously forwarded two site model of chemoldne-receptor interactions, we hypothesized that linking the agonistic N-terminus of SDF-1 to the T140 backbone would yield new high-affinity agonists of CXCR4. We developed chimeras with the agonistic SDF-1 N-terminus grafted to a T140 side chain and tested their binding affinity and chemotactic agonist activity. While chimeras with the peptide grafted onto position 12 of T140 remained high-affinity antagonists, those bearing the peptide on position 14 were in part agonists. One chimera was a full CXCR4 agonist with 25 nM affinity, and several chimeras showed low nanomolar affinities with partial agonist activity. Our results confirmed that we have developed high-affinity agonists of CXCR4.

• 出版日期2011-8