APEH catalyses the removal of N-terminal acetylated amino acids from proteins destined to be degraded and is now recognized as a new therapeutic target for several diseases. New APEH inhibitors having triazole-based structures have been recently reported. On this basis we have screened a set of click-generated cyclic peptides, previously investigated for peptide conformational stability studies, as possible novel enzyme inhibitors. We have found a clicked peptide, NHB3.3, that inhibits APEH activity and structure-activity studies highlighted that APEH inhibition is mediated by the spatial organization of the triazole ring and by its orientation and distance from the peptide scaffold, whose structural integrity, in turn, also plays a relevant role. In conclusion, our findings confirm that 1.2,3 triazoles are privileged pharmacophores for specific serine protease inhibitors and provide structural insights exploitable for modulating their inhibition activity.
