New tripeptide-based macrocyclic calpain inhibitors formed by n-alkylation of histidine

Hongyuan Chen, Wanting Jiao, Matthew A. Jones, James M. Coxon, James D. Morton, Roy Bickerstaffe, Ashok D. Pehere, Ondrej Zvarec, Andrew D. Abell

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17 Scopus citations


Two 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.

Original languageEnglish (US)
Pages (from-to)2473-2484
Number of pages12
JournalChemistry and Biodiversity
Issue number11
StatePublished - Nov 2012


  • Calpain
  • Conformation analysis
  • Inhibitors
  • Peptidomimetics
  • β-Strands


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