title: New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine.
abstract: 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 IC(50) 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.
authors.affiliation: Chemistry Department, University of Canterbury, Christchurch, New Zealand.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Chen
authors.forename: Wanting
authors.initials: W
authors.lastname: Jiao
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Jones
authors.forename: James M
authors.initials: JM
authors.lastname: Coxon
authors.forename: James D
authors.initials: JD
authors.lastname: Morton
authors.forename: Roy
authors.initials: R
authors.lastname: Bickerstaffe
authors.forename: Ashok D
authors.initials: AD
authors.lastname: Pehere
authors.forename: Ondrej
authors.initials: O
authors.lastname: Zvarec
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D000478:Alkylation; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006023:Glycoproteins / Q000737:chemistry* / Q000494:pharmacology*; D006639:Histidine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary
chemical_list: D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D047028:Macrocyclic Compounds; D057786:Peptidomimetics; C039304:calpain inhibitors; D006639:Histidine; D002154:Calpain