Journal article

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

Conan K Wang, Susan E Northfield, Joakim E Swedberg, Barbara Colless, Stephanie Chaousis, David A Price, Spiros Liras, David J Craik

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Published : 2015

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..

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Grants

Awarded by ARC Linkage Grant


Awarded by National Health and Medical Research Council (NHMRC) Early Career Research Fellowship


Funding Acknowledgements

This work was supported by an ARC Linkage Grant (LP110200213) co-funded by Pfizer and a Queensland Government Smart Futures Co-investment Grant. OM was supported by an National Health and Medical Research Council (NHMRC) Early Career Research Fellowship (546578). JES is an NHMRC Early Career Fellow (APP1069819). DJC is an NHMRC Professorial Fellow (APP1026501).