New Tripeptide-Based Macrocyclic Calpain Inhibitors Formed by N-Alkylation of Histidine

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 i...

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Bibliographic Details
Published in:Chemistry & biodiversity 2012-11, Vol.9 (11), p.2473-2484
Main Authors: Chen, Hongyuan, Jiao, Wanting, Jones, Matthew A., Coxon, James M., Morton, James D., Bickerstaffe, Roy, Pehere, Ashok D., Zvarec, Ondrej, Abell, Andrew D.
Format: Article
Language:English
Subjects:
Alkylation
Animals
Calpain
Calpain - antagonists & inhibitors
Calpain - metabolism
Conformation analysis
Cysteine Proteinase Inhibitors - chemistry
Cysteine Proteinase Inhibitors - pharmacology
Glycoproteins - chemistry
Glycoproteins - pharmacology
Histidine - chemistry
Histidine - pharmacology
Humans
Inhibitors
Macrocyclic Compounds - chemical synthesis
Macrocyclic Compounds - chemistry
Macrocyclic Compounds - pharmacology
Molecular Docking Simulation
Peptides
Peptidomimetics
Peptidomimetics - chemistry
Peptidomimetics - pharmacology
Protein Structure, Secondary
β-Strands
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Summary: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
1612-1880
DOI:10.1002/cbdv.201200320