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

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.