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

• DOI: 10.1016/j.jconrel.2024.07.049
• Publication Date: 2024-07-30T23:40:50Z
• Authors: Mirja Harms; André Haase; Armando Rodríguez...; Jessica Löffler; Yasser Almeida-He...; Yasser B. Ruiz-Bl...; Dan Albers; Andrea Gilg; Franziska von Bank; Fabian Zech; Rüdiger Groß; Moumita Datta; Janeni Jaikishan; Bastian Draphoen; Monica Habib; Ludger Ständker; Sebastian Wiese; Mika Lindén; Gordon Winter; Volker Rasche; Ambros J. Beer; Hassan Jumaa; Ashraf H. Abadi; Frank Kirchhoff; Maike Busch; Nicole Dünker; Elsa Sanchez-Garcia; Jan Münch
• Keywords: Human serum albumin; Lipid-anchored protein

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 specific endogenous antagonist, EPI-X4, addressing existing challenges stability potency. Our structure-activity relationship study investigates conjugation EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction receptor affinity. Molecular dynamic simulations revealed that lipid moieties stabilize peptide-receptor through hydrophobic contacts at receptor's N-terminus, anchoring lipopeptide within binding pocket maintaining essential interactions. Accordingly, lipidation resulted increased affinities antagonistic activities. Additionally, by interacting human lipidated displayed sustained plasma extended circulation times vivo. Selected candidates showed significant potential retinoblastoma cells vitro ovo, our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This not only elucidates optimization trajectory for but also underscores intricate interplay between efficacy, crucial delineating their translational clinical applications.