Development of N-Terminally Modified Variants of the CXCR4-Antagonistic Peptide EPI-X4 for Enhanced Plasma Stability.

Gordon Winter, Jan Münch, Alexander N Zelikin, Elsa Sanchez-Garcia, Sebastian Wiese, Ludger Ständker, Nico Preising, Gilbert Weidinger, Ambros J Beer, Volker Rasche, Mirja Harms, Ashraf H Abadi, Nermin S Ahmed, Dan Albers, Monica M W Habib, Armando Rodríguez-Alfonso, Jessica Löffler, Yasser Almeida-Hernández, Andrea Gilg, Rikke Fabech Hansson

Journal: Journal of medicinal chemistry 2023;66(22):15189-15204

PMID: 37940118

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Abstract

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 , , and 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.

Address: Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany.; Department of Chemistry and iNANO Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus 8000, Denmark.; Department of Biochemical and Chemical Engineering, Computational Bioengineering, Emil-Figge Str. 66, Dortmund 44227, Germany.; Department of Nuclear Medicine, Ulm University Medical Center, Ulm 89081, Germany.; Core Facility Functional Peptidomics, Ulm University Medical Center, Ulm 89081, Germany.; Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Ulm 89081, Germany.; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.; Pharmaceutical Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11865, Egypt.; Experimental Cardiovascular Imaging (ExCaVI), Ulm University Medical Center, Ulm 89081, Germany.; Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.

DOI: 10.1021/acs.jmedchem.3c01128

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MeSH Terms: Humans, HIV-1, Peptides, Receptors, CXCR4, Albumins, Signal Transduction, Amines, HIV Infections