Dimerization of the Peptide CXCR4-Antagonist on Macromolecular and Supramolecular Protraction Arms Affords Increased Potency and Enhanced Plasma Stability

Peptides are prime drug candidates due to their high specificity of action but are disadvantaged by low proteolytic stability. Here, we focus on the development of stabilized analogues of EPI-X4, an endogenous peptide antagonist of CXCR4. We synthesized macromolecular peptide conjugates and performe...

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Bibliographic Details
Published in:Bioconjugate chemistry 2022-04, Vol.33 (4), p.594-607
Main Authors: Harms, Mirja, Hansson, Rikke Fabech, Carmali, Sheiliza, Almeida-Hernández, Yasser, Sanchez-Garcia, Elsa, Münch, Jan, Zelikin, Alexander N
Format: Article
Language:English
Subjects:
Albumins
Antibodies
Blood plasma
Conjugates
CXCR4 protein
Dimerization
Drug development
HIV
HIV Infections
HIV-1 - physiology
Human immunodeficiency virus
Humans
Macromolecules
Magnetohydrodynamic stability
Peptides
Peptides - chemistry
Peptides - pharmacology
Proteolysis
Receptor mechanisms
Receptors
Receptors, CXCR4 - metabolism
Signal Transduction
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Summary:Peptides are prime drug candidates due to their high specificity of action but are disadvantaged by low proteolytic stability. Here, we focus on the development of stabilized analogues of EPI-X4, an endogenous peptide antagonist of CXCR4. We synthesized macromolecular peptide conjugates and performed side-by-side comparison with their albumin-binding counterparts and considered monovalent conjugates, divalent telechelic conjugates, and Y-shaped peptide dimers. All constructs were tested for competition with the CXCR4 antibody–receptor engagement, inhibition of receptor activation, and inhibition of the CXCR4-tropic human immunodeficiency virus infection. We found that the Y-shaped conjugates were more potent than the parent peptide and at the same time more stable in human plasma, with a favorable outlook for translational studies.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.2c00034