Liver microsome stability of N-methylated cyclic hexapeptides is decreased by the presence of cis-amide bonds

Huy N. Hoang; David P. Fairlie; Timothy A. Hill

doi:10.1071/CH25080

RESEARCH ARTICLE (Open Access)

Next Contents Vol 78(10)

Liver microsome stability of N-methylated cyclic hexapeptides is decreased by the presence of cis-amide bonds

Huy N. Hoang ^A ^B , David P. Fairlie ^A ^B ^* and Timothy A. Hill

^A ^B ^*

+ Author Affiliations

- Author Affiliations

^A Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.

^B Australian Research Council Centre of Excellence in Peptide and Protein Science, The University of Queensland, Brisbane, Qld 4072, Australia.

^* Correspondence to: d.fairlie@imb.uq.edu.au, t.hill@imb.uq.edu.au

Handling Editor: Ed Nice

Australian Journal of Chemistry 78, CH25080 https://doi.org/10.1071/CH25080

Submitted: 16 May 2025 Accepted: 27 August 2025 Published online: 22 September 2025

© 2025 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)

Abstract

N-methylation of cyclic peptides is a widely used strategy to enhance membrane permeability; however, it can also influence metabolic stability. In celebration of Professor David Craik’s scientific achievements – particularly in the field of peptide research – we were fortunate to gain access to a series of his cyclic peptides to investigate their liver microsomal stability. Our study revealed that the liver microsome stability of a series of 14 cyclic hexapeptides is highly variable, despite minimal differences in sequence, molecular weight and cLogP. Notably, all compounds containing cis-amide bonds exhibited very poor rat liver microsomal stability, with half-lives of less than 3 min. This work highlights a potential metabolic liability that should be taken into account when designing cyclic peptides as potential drug candidates.

Keywords: cis-amide bonds, cyclic peptides, drug clearance, hepatic metabolism, metabolic stability, n-methylation, oral bioavailability, peptide structure.

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