Orally absorbed cyclic peptides

Nielsen, Daniel S., Shepherd, Nicholas E., Xu, Weijun, Lucke, Andrew J., Stoermer, Martin J. and Fairlie, David P. (2017) Orally absorbed cyclic peptides. Chemical Reviews, 117 12: 8094-8128. doi:10.1021/acs.chemrev.6b00838


Author Nielsen, Daniel S.
Shepherd, Nicholas E.
Xu, Weijun
Lucke, Andrew J.
Stoermer, Martin J.
Fairlie, David P.
Title Orally absorbed cyclic peptides
Journal name Chemical Reviews   Check publisher's open access policy
ISSN 1520-6890
0009-2665
Publication date 2017-06-28
Year available 2017
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1021/acs.chemrev.6b00838
Open Access Status Not yet assessed
Volume 117
Issue 12
Start page 8094
End page 8128
Total pages 35
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Subject 1600 Chemistry
Abstract Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol–water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.
Keyword Chemistry, Multidisciplinary
Chemistry
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1027369
1117017
CE140100011
DP130100629
DP150104609
DP160104442
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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