Structure–Activity Relationship and Signaling of New Chimeric CXCR4 Agonists

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• 作者：Christine E. Mona ; Élie Besserer-Offroy ; Jérôme Cabana ; Marilou Lefrançois ; Philip E. Boulais ; Marie-Reine Lefebvre ; Richard Leduc ; Pierre Lavigne ; Nikolaus Heveker ; Éric Marsault ; Emanuel Escher
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7512-7524
• 全文大小：668K
• 年卷期：0
• ISSN：1520-4804

文摘

The CXCR4 receptor binds with meaningful affinities only CXCL12 and synthetic antagonists/inverse agonists. We recently described high affinity synthetic agonists for this chemokine receptor, obtained by grafting the CXCL12 N-terminus onto the inverse agonist T140. While those chimeric molecules behave as agonists for CXCR4, their binding and activation mode are unknown. The present SAR of those CXCL12-oligopeptide grafts reveals the key determinants involved in CXCR4 activation. Position 3 (Val) controls affinity, whereas position 7 (Tyr) acts as an efficacy switch. Chimeric molecules bearing aromatic residues in position 3 possess high binding affinities for CXCR4 and are Gα_i full agonists with robust chemotactic properties. Fine-tuning of electron-poor aromatic rings in position 7 enhances receptor activation. To rationalize these results, a homology model of a receptor–ligand complex was built using the published crystal structures of CXCR4. Molecular dynamics simulations reveal further details accounting for the observed SAR for this series.