Improving on nature: making a cyclic heptapeptide orally bioavailable.
Angew Chem Int Ed Engl
; 53(45): 12059-63, 2014 Nov 03.
Article
en En
| MEDLINE
| ID: mdl-25219505
ABSTRACT
The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oligopéptidos
/
Péptidos Cíclicos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2014
Tipo del documento:
Article