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https://hdl.handle.net/2440/74977
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Type: | Journal article |
Title: | New tripeptide-based macrocyclic calpain inhibitors formed by n-alkylation of histidine |
Author: | Chen, H. Jiao, W. Jones, M. Coxon, J. Morton, J. Bickerstaffe, R. Pehere, A. Zvarec, O. Abell, A. |
Citation: | Chemistry and Biodiversity, 2012; 9(11):2473-2484 |
Publisher: | Wiley - V C H Verlag GmbH & Co. KGaA |
Issue Date: | 2012 |
ISSN: | 1612-1872 1612-1880 |
Statement of Responsibility: | Hongyuan Chen, Wanting Jiao, Matthew A. Jones, James M. Coxon, James D. Morton, Roy Bickerstaffe, Ashok D. Pehere, Ondrej Zvarec and Andrew D. Abell |
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. |
Keywords: | Peptidomimetics Conformation analysis Inhibitors Calpain β-Strands |
Rights: | Copyright © 2012 Verlag Helvetica Chimica Acta AG, Zürich |
DOI: | 10.1002/cbdv.201200320 |
Published version: | http://dx.doi.org/10.1002/cbdv.201200320 |
Appears in Collections: | Aurora harvest IPAS publications |
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