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Pyridyl-alanine as a Hydrophilic, Aromatic Element in Peptide Structural Optimization.
J Med Chem ; 59(17): 8061-7, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27509198
Glucagon (Gcg) 1 serves a seminal physiological role in buffering against hypoglycemia, but its poor biophysical properties severely complicate its medicinal use. We report a series of novel glucagon analogues of enhanced aqueous solubility and stability at neutral pH, anchored by Gcg[Aib16]. Incorporation of 3- and 4-pyridyl-alanine (3-Pal and 4-Pal) enhanced aqueous solubility of glucagon while maintaining biological properties. Relative to native hormone, analogue 9 (Gcg[3-Pal6,10,13, Aib16]) demonstrated superior biophysical character, better suitability for medicinal purposes, and comparable pharmacology against insulin-induced hypoglycemia in rats and pigs. Our data indicate that Pal is a versatile surrogate to natural aromatic amino acids and can be employed as an alternative or supplement with isoelectric adjustment to refine the biophysical character of peptide drug candidates.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Piridinas / Glucagon / Alanina / Hipoglicemia Limite: Animais / Humanos / Masculino Idioma: Inglês Revista: J Med Chem Assunto da revista: Química Ano de publicação: 2016 Tipo de documento: Artigo