title: Pyridyl-alanine as a Hydrophilic, Aromatic Element in Peptide Structural Optimization.
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.
authors: Department of Chemistry, Indiana University , 800 East Kirkwood, Bloomington, Indiana 47405 United States.
authors: Piotr A
authors: PA
authors: Mroz
authors: Department of Medicine, Metabolic Diseases Institute, University of Cincinnati , Cincinnati, Ohio 45267 United States.
authors: Diego
authors: D
authors: Perez-Tilve
authors: Novo Nordisk Research Center , Indianapolis, Indiana 46241, United States.
authors: Fa
authors: F
authors: Liu
authors: Novo Nordisk Research Center , Indianapolis, Indiana 46241, United States.
authors: Vasily
authors: V
authors: Gelfanov
authors: Department of Chemistry, Indiana University , 800 East Kirkwood, Bloomington, Indiana 47405 United States.|Novo Nordisk Research Center , Indianapolis, Indiana 46241, United States.
authors: Richard D
authors: RD
authors: DiMarchi
authors: Novo Nordisk Research Center , Indianapolis, Indiana 46241, United States.
authors: John P
authors: JP
authors: Mayer
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004355:Drug Stability; D005934:Glucagon / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy*; D008297:Male; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D060327:Solid-Phase Synthesis Techniques; D012995:Solubility; D013552:Swine
chemical_list: C115669:4-pyridyl-alanine; D011725:Pyridines; C012787:3-pyridylalanine; D005934:Glucagon; D000242:Cyclic AMP; D000409:Alanine