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

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. O...

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Published in:	Journal of controlled release Vol. 373; pp. 583 - 598
Main Authors:	Harms, Mirja, Haase, André, Rodríguez-Alfonso, Armando, Löffler, Jessica, Almeida-Hernández, Yasser, Ruiz-Blanco, Yasser B., Albers, Dan, Gilg, Andrea, von Bank, Franziska, Zech, Fabian, Groß, Rüdiger, Datta, Moumita, Jaikishan, Janeni, Draphoen, Bastian, Habib, Monica, Ständker, Ludger, Wiese, Sebastian, Lindén, Mika, Winter, Gordon, Rasche, Volker, Beer, Ambros J., Jumaa, Hassan, Abadi, Ashraf H., Kirchhoff, Frank, Busch, Maike, Dünker, Nicole, Sanchez-Garcia, Elsa, Münch, Jan
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-09-2024
Subjects:	Animals Cell Line, Tumor CXCR4 Drug Stability EPI-X4 Fatty Acids - chemistry Female Humans Lipidation Lipopeptides - chemistry Lipopeptides - pharmacology Molecular Dynamics Simulation Receptors, CXCR4 - antagonists & inhibitors Receptors, CXCR4 - metabolism Retinoblastoma Serum albumin Structure-Activity Relationship CXCR4 Serum albumin EPI-X4 Retinoblastoma Lipidation
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Summary:	Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity. Molecular dynamic simulations revealed that the lipid moieties stabilize the peptide-receptor interaction through hydrophobic contacts at the receptor's N-terminus, anchoring the lipopeptide within the CXCR4 binding pocket and maintaining essential receptor interactions. Accordingly, lipidation resulted in increased receptor affinities and antagonistic activities. Additionally, by interacting with human serum albumin lipidated EPI-X4 derivatives displayed sustained stability in human plasma and extended circulation times in vivo. Selected candidates showed significant therapeutic potential in human retinoblastoma cells in vitro and in ovo, with our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This study not only elucidates the optimization trajectory for EPI-X4 derivatives but also underscores the intricate interplay between stability and efficacy, crucial for delineating their translational potential in clinical applications. [Display omitted] •Lipidated derivatives of EPI-X4 exhibit increased affinity and antagonistic activity towards the CXCR4 receptor.•Lipidated EPI-X4 derivatives exhibit a half-life of >8 h in both blood and plasma.•The lipidated EPI-X4 JM#198 displays a circulation half-life of nearly 4 h in mice.•EPI-X4 JM#198 inhibits retinoblastoma tumor formation in vitro and in ovo.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0168-3659 1873-4995 1873-4995
DOI:	10.1016/j.jconrel.2024.07.049