التفاصيل البيبلوغرافية
| العنوان: |
Development of N-terminally modified variants of the CXCR4-antagonizing peptide EPI-X4 with increased plasma stability |
| المؤلفون: |
Harms, Mirja, Almeida-Hernández, Yasser, Alfonso, Armando Rodríguez, Habib, Monica, Gilg, Andrea, Albers, Dan, Ahmed, Nermin, Abadi, Ashraf, Weidinger, Gilbert, Ständker, Ludger, Wiese, Sebastian, Sanchez-Garcia, Elsa, Münch, Jan |
| بيانات النشر: |
Authorea, Inc. |
| سنة النشر: |
2022 |
| المجموعة: |
The Winnower (via CrossRef) |
| الوصف: |
EPI-X4 is a natural peptide antagonist of CXCR4, an established drug target in inflammatory diseases and cancer. Advanced derivatives of EPI-X4, such as EPI-X4 JM#21, have shown promising therapeutic effects in animal models of CXCR4-associated diseases but suffer from poor stability in blood. We here aimed to design and characterize EPI-X4 analogs that effectively antagonize CXCR4 while remaining stable in human plasma. We found that EPI-X4 analogs are stable against degradation by endopeptidases. However derivatives are are prone to degradation by exopeptidases which target the peptides’ N- but not the C-terminus. Modifications of the peptide N-terminus by introducing D-amino acids or acetyl residues resulted in EPI-X4 derivatives with greatly enhanced plasma stability. The identified lead candidates EPI-X4 JM#29, JM#173, and JM#174, which contain D-amino acids L or I at position 1, were as active in binding and antagonizing CXCR4 as EPI-X4 JM#21, and remained active even after 8 hours of incubation in plasma. Molecular dynamics simulations showed that the binding mode of these stabilized EPI-X4 derivatives to CXCR4 is similar to the binding of JM#21. The peptides establish conserved interactions with acidic residues in the minor subpocket and the extracellular loops 1 and 2 of the receptor. None of the novel EPI-X4 leads showed any signs of toxicity in zebrafish embryos, paving the way for further evaluation of the pharmacokinetic and therapeutic properties of this new generation of EPI-X4 analogs in rodent models. |
| نوع الوثيقة: |
other/unknown material |
| اللغة: |
unknown |
| DOI: |
10.22541/au.166733107.78559129/v1 |
| الإتاحة: |
https://doi.org/10.22541/au.166733107.78559129/v1Test |
| رقم الانضمام: |
edsbas.7F6B3A9C |
| قاعدة البيانات: |
BASE |
