化学
肽
对抗
CXCR4拮抗剂
白蛋白
敌手
CXCR4型
组合化学
生物化学
立体化学
受体
趋化因子
作者
Mirja Harms,Rikke Fabech Hansson,Andrea Gilg,Yasser Almeida‐Hernández,Jessica Löffler,Armando A. Rodríguez,Monica Habib,Dan Albers,Nermin S. Ahmed,Ashraf H. Abadi,Gordon Winter,Volker Rasche,Ambros J. Beer,Gilbert Weidinger,Nico Preising,Ludger Ständker,Sebastian Wiese,Elsa Sánchez-García,Alexander N. Zelikin,Jan Münch
标识
DOI:10.1021/acs.jmedchem.3c01128
摘要
EPI-X4, a natural peptide CXCR4 antagonist, shows potential for treating inflammation and cancer, but its short plasma stability limits its clinical application. We aimed to improve the plasma stability of EPI-X4 analogues without compromising CXCR4 antagonism. Our findings revealed that only the peptide N-terminus is prone to degradation. Consequently, incorporating d-amino acids or acetyl groups in this region enhanced peptide stability in plasma. Notably, EPI-X4 leads 5, 27, and 28 not only retained their CXCR4 binding and antagonism but also remained stable in plasma for over 8 h. Molecular dynamic simulations showed that these modified analogues bind similarly to CXCR4 as the original peptide. To further increase their systemic half-lives, we conjugated these stabilized analogues with large polymers and albumin binders. These advances highlight the potential of the optimized EPI-X4 analogues as promising CXCR4-targeted therapeutics and set the stage for more detailed preclinical assessments.
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