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Microsome stability of n-methylated cyclic hexapeptides is decreased by the presence of cis-amide bonds

Huy Hoang, David Fairlie, Tim Hill

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 three minutes. This work highlights a potential metabolic liability that should be taken into account when designing cyclic peptides as potential drug candidates

CH25080  Accepted 27 August 2025

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