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Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable
Author(s) -
Nielsen Daniel S.,
Hoang Huy N.,
Lohman RinkJan,
Hill Timothy A.,
Lucke Andrew J.,
Craik David J.,
Edmonds David J.,
Griffith David A.,
Rotter Charles J.,
Ruggeri Roger B.,
Price David A.,
Liras Spiros,
Fairlie David P.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201405364
Subject(s) - bioavailability , chemistry , intramolecular force , amide , metabolic stability , membrane permeability , hydrogen bond , stereochemistry , combinatorial chemistry , organic chemistry , membrane , pharmacology , molecule , biochemistry , medicine , in vitro
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.