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d-Amino acid substitutions and dimerization increase the biological activity and stability of an IL-15 antagonist peptide.
Rodríguez-Álvarez, Yunier; Cabrales-Rico, Ania; Diago-Abreu, David; Correa-Arguelles, Elianys; Reyes-Acosta, Osvaldo; Puente-Pérez, Pedro; Pichardo-Díaz, Dagmara; Urquiza-Noa, Dioslaida; Hernández-Santana, Amalia; Garay-Pérez, Hilda E.
Afiliação
  • Rodríguez-Álvarez Y; Pharmaceutical Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Cabrales-Rico A; Chemistry and Physics Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Diago-Abreu D; Chemistry and Physics Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Correa-Arguelles E; Pharmaceutical Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Reyes-Acosta O; Chemistry and Physics Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Puente-Pérez P; Animal Facility Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Pichardo-Díaz D; Animal Facility Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Urquiza-Noa D; Animal Facility Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Hernández-Santana A; Animal Facility Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
  • Garay-Pérez HE; Chemistry and Physics Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
J Pept Sci ; 27(3): e3293, 2021 Mar.
Article em En | MEDLINE | ID: mdl-33331098
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos / Interleucina-15 Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Pept Sci Assunto da revista: BIOQUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Cuba País de publicação: Reino Unido
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeos / Interleucina-15 Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Pept Sci Assunto da revista: BIOQUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Cuba País de publicação: Reino Unido