Pyridyl-alanine as a Hydrophilic, Aromatic Element in Peptide Structural Optimization.
Basic Information
ID: ALA4431340
Journal: J Med Chem
Title: Pyridyl-alanine as a Hydrophilic, Aromatic Element in Peptide Structural Optimization.
Authors: Mroz PA, Perez-Tilve D, Liu F, Gelfanov V, DiMarchi RD, Mayer JP.
Abstract: 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.
CiteXplore: 27509198
DOI: 10.1021/acs.jmedchem.6b00840
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