Artikel ; Online: d-Amino acid substitutions and dimerization increase the biological activity and stability of an IL-15 antagonist peptide.
Journal of peptide science : an official publication of the European Peptide Society
2020 Band 27, Heft 3, Seite(n) e3293
Abstract: Interleukin (IL)-15 plays an important role in several inflammatory diseases. We have previously identified an IL-15 antagonist called P8 peptide, which binds specifically to IL-15 receptor alpha subunit. However, the P8 peptide rapidly degraded by ... ...
| Abstract | Interleukin (IL)-15 plays an important role in several inflammatory diseases. We have previously identified an IL-15 antagonist called P8 peptide, which binds specifically to IL-15 receptor alpha subunit. However, the P8 peptide rapidly degraded by proteases, limiting its therapeutic application. Thus, we replaced each P8 peptide l-amino acid by its corresponding d-isomers. First, we determined the biological activity of the resulting peptides in a proliferation assay by using CTLL-2 cells. The substitution of l-Ala by d-Ala ([A4a]P8 peptide) increased the inhibitory effect of the P8 peptide in CTLL-2 cells in five-fold. In addition to that, the [A4a]P8 peptide dimer showed the most inhibitory effect. To protect the [A4a]P8 peptide and its dimer against exopeptidase activity, we acetylated the N-terminal of these peptides. At least a three-fold reduction in antagonist activity of acetylated peptides was exhibited. However, the substitution of the N-terminal l-Lys residue of [A4a]P8 peptide and its dimer by d-Lys ([K1k;A4a]P8 peptide) did not affect the antagonist effect of the aforementioned peptides. The [K1k;A4a]P8 peptide dimer was stable to the degradation of trypsin, chymotrypsin, and pepsin up until 48 min. Also, the safety and immunogenicity studies in healthy BALB/c mice demonstrated that the administration of this peptide did not affect the clinical parameters of the animals nor generated antipeptide antibodies. Our findings reveal that two distinct d-amino acid substitutions and dimerization increase the biological activity and stability of P8 peptide. The resulting peptide constitutes a novel IL-15 antagonist with potential applicability in inflammatory diseases. |
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| Mesh-Begriff(e) | Amino Acid Substitution/drug effects ; Animals ; Cell Line ; Cell Proliferation/drug effects ; Dimerization ; Female ; Interleukin-15/antagonists & inhibitors ; Interleukin-15/metabolism ; Mice ; Mice, Inbred BALB C ; Peptides/chemical synthesis ; Peptides/chemistry ; Peptides/pharmacology | |||||
| Chemische Substanzen | Interleukin-15 ; Peptides | |||||
| Sprache | Englisch | |||||
| Erscheinungsdatum | 2020-12-16 | |||||
| Erscheinungsland | England | |||||
| Dokumenttyp | Journal Article | |||||
| ZDB-ID | 1234416-3 | |||||
| ISSN | 1099-1387 ; 1075-2617 | |||||
| ISSN (online) | 1099-1387 | |||||
| ISSN | 1075-2617 | |||||
| DOI | 10.1002/psc.3293 | |||||
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| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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