Chen, HongyuanJiao, WJones, MACoxon, JMMorton, JamesBickerstaffe, RPehere, ADZvarec, OAbell, AD2017-07-122012-11-192012-11Chen et al. (2012). New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine. Chemistry and Biodiversity, 9, 2473-2484. doi:10.1002/cbdv.2012003201612-187223161629 (pubmed)https://hdl.handle.net/10182/8299Two new series of 15-membered macrocyclic peptidomimetics, in which the P1 and P3 residues of the peptide backbone are linked by a bridge containing a 1,4-disubstituted 1H-imidazole, are reported. The structure with an aldehyde at the C-terminus and the imidazole at P3, i.e., 4c, shows significant inhibitory activity against calpain 2, with an IC₅₀ value of 238 nM. The macrocyclic aldehyde with the imidazole at the alternative P1 position, i.e., 5c, is significantly less active. The relative activities are linked to the ability of the component macrocycles to mimic a β-strand geometry that is known to favor active-site binding. This ability is defined by conformational searches and docking studies with calpain.pp.2473-2484Printen© Verlag Helvetica Chimica Acta AG, Zurichmacrocyclic peptidomimeticsN-alkylation of histidinecalpaininhibitory activitytripeptide-based macrocyclic calpain inhibitorspeptideAnimalsHumansMacrocyclic CompoundsCalpainGlycoproteinsHistidineCysteine Proteinase InhibitorsProtein Structure, SecondaryAlkylationPeptidomimeticsMolecular Docking SimulationJournal Article10.1002/cbdv.201200320ANZSRC::030405 Molecular MedicineANZSRC::030406 Proteins and Peptides1612-1880ANZSRC::3404 Medicinal and biomolecular chemistryANZSRC::3405 Organic chemistry