Exploring experimental and computational markers of cyclic peptides: charting islands of permeability

Wang, Conan K., Northfield, Susan Ellen, Swedberg, Joakim E., Colless, Barbara, Chaousis, Stephanie, Price, David A., Liras, Spiros and Craik, David J. (2015) Exploring experimental and computational markers of cyclic peptides: charting islands of permeability. European Journal of Medicinal Chemistry, 97 202-213. doi:10.1016/j.ejmech.2015.04.049

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Author Wang, Conan K.
Northfield, Susan Ellen
Swedberg, Joakim E.
Colless, Barbara
Chaousis, Stephanie
Price, David A.
Liras, Spiros
Craik, David J.
Title Exploring experimental and computational markers of cyclic peptides: charting islands of permeability
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 1768-3254
Publication date 2015-05
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2015.04.049
Open Access Status File (Author Post-print)
Volume 97
Start page 202
End page 213
Total pages 12
Place of publication Issy les Moulineaux, Cedex, France
Publisher Elsevier Masson
Collection year 2016
Language eng
Abstract An increasing number of macrocyclic peptides that cross biological membranes are being reported, suggesting that it might be possible to develop peptides into orally bioavailable therapeutics; however, current understanding of what makes macrocyclic peptides cell permeable is still limited. Here, we synthesized 62 cyclic hexapeptides and characterized their permeability using in vitro assays commonly used to predict in vivo absorption rates, i.e. the Caco-2 and PAMPA assays. We correlated permeability with experimentally measured parameters of peptide conformation obtained using rapid methods based on chromatography and nuclear magnetic resonance spectroscopy. Based on these correlations, we propose a model describing the interplay between peptide permeability, lipophilicity and hydrogen bonding potential. Specifically, peptides with very high permeability have high lipophilicity and few solvent hydrogen bond interactions, whereas peptides with very low permeability have low lipophilicity or many solvent interactions. Our model is supported by molecular dynamics simulations of the cyclic peptides calculated in explicit solvent, providing a structural basis for the observed correlations. This prospective exploration into biomarkers of peptide permeability has the potential to unlock wider opportunities for development of peptides into drugs.
Keyword Amide temperature coefficients
Cyclic peptide
Drug design
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
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