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Fatty acid conjugated EPI-X4 derivatives with increased activity and in vivo stability

Mirja Harms1, André Haase2, Armando Rodríguez-Alfonso3

  • 1Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|July 24, 2024
PubMed

Insights

Optimized EPI-X4 peptide variants with fatty acids show enhanced CXCR4 antagonism and stability. These lipopeptides demonstrate therapeutic potential for diseases involving the CXCL12/CXCR4 axis.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • The CXCL12/CXCR4 signaling pathway is crucial in various diseases, including cancer and autoimmune disorders.
  • CXCR4 is a key therapeutic target due to its role in disease pathogenesis.
  • Existing CXCR4 antagonists face challenges in stability and potency.

Purpose of the Study:

  • To optimize the endogenous CXCR4 antagonist EPI-X4 for improved stability and efficacy.
  • To investigate the structure-activity relationships of EPI-X4 derivatives.
  • To explore the therapeutic potential of modified EPI-X4 in disease models.

Main Methods:

  • Structure-activity relationship studies involving conjugation of EPI-X4 with fatty acids.
  • Molecular dynamic simulations to analyze peptide-receptor interactions.
  • In vitro and in ovo assays using human retinoblastoma cells.
  • In vivo pharmacokinetic studies assessing plasma stability and circulation time.

Main Results:

  • Lipidation of EPI-X4 derivatives enhanced receptor affinity and antagonistic activity.
  • Molecular simulations showed lipid moieties stabilize interactions within the CXCR4 binding pocket.
  • Lipidated EPI-X4 exhibited increased stability in human plasma and prolonged circulation.
  • Selected candidates demonstrated significant therapeutic efficacy in retinoblastoma models.

Conclusions:

  • Fatty acid conjugation is an effective strategy to enhance the stability and efficacy of EPI-X4.
  • Lipidated EPI-X4 derivatives show promise as therapeutic agents targeting the CXCR4 pathway.
  • The findings highlight the importance of optimizing peptide stability for clinical translation.
Keywords:
CXCR4EPI-X4LipidationRetinoblastomaSerum albumin

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