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

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

  • J Med Chem. 2023 Nov 23;66(22):15189-15204. doi: 10.1021/acs.jmedchem.3c01128.
Mirja Harms 1,  Rikke Fabech Hansson 2,  Andrea Gilg 1,  Yasser Almeida-Hernández 3,  Jessica Löffler 4,  Armando Rodríguez-Alfonso 5 6,  Monica M W Habib 7 8,  Dan Albers 1,  Nermin S Ahmed 7,  Ashraf H Abadi 7,  Gordon Winter 4,  Volker Rasche 9,  Ambros J Beer 4,  Gilbert Weidinger 10,  Nico Preising 5,  Ludger Ständker 5,  Sebastian Wiese 6,  Elsa Sanchez-Garcia 3,  Alexander N Zelikin 2,  Jan Münch 1 5
Affiliations

Affiliations

  • 1 Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany.
  • 2 Department of Chemistry and iNANO Interdisciplinary Nanoscience Centre, Aarhus University, Aarhus 8000, Denmark.
  • 3 Department of Biochemical and Chemical Engineering, Computational Bioengineering, Emil-Figge Str. 66, Dortmund 44227, Germany.
  • 4 Department of Nuclear Medicine, Ulm University Medical Center, Ulm 89081, Germany.
  • 5 Core Facility Functional Peptidomics, Ulm University Medical Center, Ulm 89081, Germany.
  • 6 Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Ulm 89081, Germany.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
  • 8 Pharmaceutical Chemistry Department, School of Life and Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, Cairo 11865, Egypt.
  • 9 Experimental Cardiovascular Imaging (ExCaVI), Ulm University Medical Center, Ulm 89081, Germany.
  • 10 Institute of Biochemistry and Molecular Biology, Ulm University, Ulm 89081, Germany.
PMID: 37940118 DOI: 10.1021/acs.jmedchem.3c01128
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 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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