Improving on nature: making a cyclic heptapeptide orally bioavailable

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 and Fairlie, David P. (2014) Improving on nature: making a cyclic heptapeptide orally bioavailable. Angewandte Chemie - International Edition, 53 45: 12059-12063. doi:10.1002/anie.201405364

Author 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.
Title Improving on nature: making a cyclic heptapeptide orally bioavailable
Journal name Angewandte Chemie - International Edition   Check publisher's open access policy
ISSN 1521-3773
Publication date 2014-11-01
Sub-type Article (original research)
DOI 10.1002/anie.201405364
Open Access Status
Volume 53
Issue 45
Start page 12059
End page 12063
Total pages 5
Place of publication Weinheim, Germany
Publisher Wiley-VCH Verlag
Collection year 2015
Language eng
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.
Keyword Cyclic peptides
Oral bioavailability
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 09 Dec 2014, 14:03:03 EST by Susan Allen on behalf of Institute for Molecular Bioscience