Details

Autor(en) / Beteiligte

• Nielsen, Daniel S.
• Hoang, Huy N.
• Lohman, Rink-Jan
• 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.

Titel

Improving on Nature: Making a Cyclic Heptapeptide Orally Bioavailable

Ist Teil von

• Angewandte Chemie (International ed.), 2014-11, Vol.53 (45), p.12059-12063

Auflage

International ed. in English

Ort / Verlag

Weinheim: WILEY-VCH Verlag

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. The oral absorption and bioavailability of a cyclic heptapeptide in rats was improved by combining heterocyclic constraints, intramolecular hydrogen bonds, and branched amino acid side chains to shield polar backbone atoms. These improvements were solely guided by amide H–D exchange rates, NMR‐derived structures, and solvent‐exposed polar surfaces.