ArticleCommunications biology2021
Computational modeling and experimental validation of the EPI-X4/CXCR4 complex allows rational design of small peptide antagonists.
Article in Communications biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- CXCR4: A Promising Novel Strategy for Lung Cancer Treatment.Biomolecules · 2026Review
- Comprehensive In Silico Analysis of the CXCL12, C55Y Mutation Reveals Structural and Functional Disruption in CXCR4/CXCR7 Signaling.Evolutionary bioinformatics online · 2026Article
- A Computational Perspective to Intermolecular Interactions and the Role of the Solvent on Regulating Protein Properties.Chemical reviews · 2025Review
- CXCR4 Inhibition Enhances the Efficacy of CD19 Monoclonal Antibody-Mediated Extermination of B-Cell Lymphoma.International journal of molecular sciences · 2025Article
- Development of N-Terminally Modified Variants of the CXCR4-Antagonistic Peptide EPI-X4 for Enhanced Plasma Stability.Journal of medicinal chemistry · 2023Article
- Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study.Medicina (Kaunas, Lithuania) · 2023Article
- Conformational States of the CXCR4 Inhibitor Peptide EPI-X4-A Theoretical Analysis.International journal of molecular sciences · 2023Article
- Article
- Peptide Bispecifics Inhibiting HIV-1 Infection by an Orthogonal Chemical and Supramolecular Strategy.Bioconjugate chemistry · 2023Article
- Development of a New Class of CXCR4-Targeting Radioligands Based on the Endogenous Antagonist EPI-X4 for Oncological Applications.Journal of medicinal chemistry · 2023Article
- Spermine and spermidine bind CXCR4 and inhibit CXCR4- but not CCR5-tropic HIV-1 infection.Science advances · 2023Article
- Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation.Frontiers in immunology · 2023Review
- Article
- Advanced EPI-X4 Derivatives Covalently Bind Human Serum Albumin Resulting in Prolonged Plasma Stability.International journal of molecular sciences · 2022Article
- PPI-Affinity: A Web Tool for the Prediction and Optimization of Protein-Peptide and Protein-Protein Binding Affinity.Journal of proteome research · 2022Article
- CXCR4 as a novel target in immunology: moving away from typical antagonists.Future drug discovery · 2022Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
EPI-X4, a 16-mer fragment of albumin, is a specific endogenous antagonist and inverse agonist of the CXC-motif-chemokine receptor 4 (CXCR4) and thus a key regulator of CXCR4 function. Accordingly, activity-optimized synthetic derivatives of EPI-X4 are promising leads for the therapy of CXCR4-linked disorders such as cancer or inflammatory diseases. We investigated the binding of EPI-X4 to CXCR4, which so far remained unclear, by means of biomolecular simulations combined with experimental mutagenesis and activity studies. We found that EPI-X4 interacts through its N-terminal residues with CXCR4 and identified its key interaction motifs, explaining receptor antagonization. Using this model, we developed shortened EPI-X4 derivatives (7-mers) with optimized receptor antagonizing properties as new leads for the development of CXCR4 inhibitors. Our work reveals the molecular details and mechanism by which the first endogenous peptide antagonist of CXCR4 interacts with its receptor and provides a foundation for the rational design of improved EPI-X4 derivatives.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.