title: Native Design of Soluble, Aggregation-Resistant Bioactive Peptides: Chemical Evolution of Human Glucagon.
abstract: Peptide-based therapeutics commonly suffer from biophysical properties that compromise pharmacology and medicinal use. Structural optimization of the primary sequence is the usual route to address such challenges while trying to maintain as much native character and avoiding introduction of any foreign element that might evoke an immunological response. Glucagon serves a seminal physiological role in buffering against hypoglycemia, but its low aqueous solubility, chemical instability, and propensity to self-aggregate severely complicate its medicinal use. Selective amide bond replacement with metastable ester bonds is a preferred approach to the preparation of peptides with biophysical properties that otherwise inhibit synthesis. We have recruited such chemistry in the design and development of unique glucagon prodrugs that have physical properties suitable for medicinal use and yet rapidly convert to native hormone upon exposure to slightly alkaline pH. These prodrugs demonstrate in vitro and in vivo pharmacology when formulated in physiological buffers that are nearly identical to native hormone when solubilized in conventional dilute hydrochloric acid. This approach provides the best of both worlds, where the pro-drug delivers chemical properties supportive of aqueous formulation and the native biological properties.
authors: Department of Chemistry, Indiana University , 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: John P
authors: JP
authors: Mayer
authors: Department of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.|Novo Nordisk Research Center , Indianapolis, Indiana 46241, United States.
authors: Richard D
authors: RD
authors: DiMarchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D005765:Gastrointestinal Agents / Q000737:chemistry* / Q000494:pharmacology*; D005934:Glucagon / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007003:Hypoglycemia / Q000188:drug therapy / Q000378:metabolism; D008958:Models, Molecular; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D012995:Solubility
chemical_list: D001786:Blood Glucose; D005765:Gastrointestinal Agents; D011355:Prodrugs; D005934:Glucagon