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Title: New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine
Authors: Chen, Hongyuan
Jiao, Wanting
Bickerstaffe, Roy
Zvarec, Ondrej
Jones, Matthew A.
Coxon, James M.
Morton, James D.
Pehere, Ashok D.
Abell, Andrew D.
Issue Date: 2012
Source: Chen, H., Jiao, W., Jones, M. A., Coxon, J. M., Morton, J. D., Bickerstaffe, R., Pehere, A. D., Zvarec, O.,& Abell, A. D. (2012). New Tripeptide-Based Macrocyclic Calpain Inhibitors Formed by N-Alkylation of Histidine. Chemistry & Biodiversity, 9(11), 2473-2484.
Series/Report no.: Chemistry & biodiversity
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 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.
ISSN: 1612-1872
DOI: 10.1002/cbdv.201200320
Fulltext Permission: none
Fulltext Availability: No Fulltext
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