New Tripeptide‐Based Macrocyclic Calpain Inhibitors Formed by N‐Alkylation of Histidine |
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| Authors: | 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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| Institution: | 1. Chemistry Department, University of Canterbury, Christchurch, New Zealand;2. Present address: Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA.;3. University of Roehampton, London, UK;4. Lincoln University, Lincoln, New Zealand;5. School of Chemistry and Physics, University of Adelaide, South Australia, Australia;6. Present address: School of Materials, Science and Engineering, Nanyang Technological University, Singapore.;7. Present address: School of Chemistry and Physics, University of Adelaide, South Australia, Australia. |
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| 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. |
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| Keywords: | Peptidomimetics Conformation analysis Inhibitors Calpain β ‐Strands |
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