Enhancement of the inhibitory effect of an IL-15 antagonist peptide by alanine scanning
| Autor: | Alicia Santos, Savio, Osvaldo Reyes, Acosta, Haydee Gerónimo, Pérez, Yunier Rodríguez, Alvarez, Araceli, Chico, Hilda Garay, Pérez, Miriam Ojeda, Ojeda, Celia Aurora Arrieta, Aguero, Miguel, Estévez, Gerardo Guillen, Nieto |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Interleukin-15
Threonine Alanine Tumor Necrosis Factor-alpha Lysine T-Lymphocytes Molecular Sequence Data Enzyme-Linked Immunosorbent Assay Cell Line Arthritis Rheumatoid Inhibitory Concentration 50 Structure-Activity Relationship Interleukin-15 Receptor alpha Subunit Synovial Fluid Humans Amino Acid Sequence Peptides Chromatography High Pressure Liquid Protein Binding |
| Zdroj: | Journal of peptide science : an official publication of the European Peptide Society. 18(1) |
| ISSN: | 1099-1387 |
| Popis: | IL-15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL-15 antagonist peptide corresponding to sequence 36-45 of IL-15 (KVTAMKCFLL) named P8, which specifically binds to IL-15Rα and inhibits IL-15 biological activity with a half maximal inhibitory concentration (IC50) of 130 µ m in CTLL-2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL-15Rα, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect. Here, we found that Phe and Cys are important for peptide binding to IL-15Rα. We also investigated other single site mutations and replaced the second Lys in the sequence by the polar non-charged amino acid threonine. The resulting peptide [K6T]P8 exhibited a higher activity than P8 with an IC50 of 24 µm. We also found that this peptide was more active than peptide P8 in the inhibition of TNFα secretion by synovial cells from rheumatoid arthritis patients. The peptide [K6T]P8 described in this work is a new type of IL-15 antagonist and constitutes a potential therapeutic agent for rheumatoid arthritis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text