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...
| Main Authors: | , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2013
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| Online Access: | https://hdl.handle.net/10356/96707 http://hdl.handle.net/10220/13036 |
| _version_ | 1811682144890650624 |
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| author | Chen, Hongyuan Jiao, Wanting Bickerstaffe, Roy Zvarec, Ondrej Jones, Matthew A. Coxon, James M. Morton, James D. Pehere, Ashok D. Abell, Andrew D. |
| author2 | School of Materials Science & Engineering |
| author_facet | School of Materials Science & Engineering Chen, Hongyuan Jiao, Wanting Bickerstaffe, Roy Zvarec, Ondrej Jones, Matthew A. Coxon, James M. Morton, James D. Pehere, Ashok D. Abell, Andrew D. |
| author_sort | Chen, Hongyuan |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T03:52:11Z |
| format | Journal Article |
| id | ntu-10356/96707 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:52:11Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/967072020-06-01T10:21:10Z New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine Chen, Hongyuan Jiao, Wanting Bickerstaffe, Roy Zvarec, Ondrej Jones, Matthew A. Coxon, James M. Morton, James D. Pehere, Ashok D. Abell, Andrew D. School of Materials Science & Engineering 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. 2013-08-06T03:32:22Z 2019-12-06T19:34:08Z 2013-08-06T03:32:22Z 2019-12-06T19:34:08Z 2012 2012 Journal Article 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. 1612-1872 https://hdl.handle.net/10356/96707 http://hdl.handle.net/10220/13036 10.1002/cbdv.201200320 en Chemistry & biodiversity |
| spellingShingle | Chen, Hongyuan Jiao, Wanting Bickerstaffe, Roy Zvarec, Ondrej Jones, Matthew A. Coxon, James M. Morton, James D. Pehere, Ashok D. Abell, Andrew D. New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine |
| title | New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine |
| title_full | New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine |
| title_fullStr | New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine |
| title_full_unstemmed | New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine |
| title_short | New tripeptide-based macrocyclic calpain inhibitors formed by N-alkylation of histidine |
| title_sort | new tripeptide based macrocyclic calpain inhibitors formed by n alkylation of histidine |
| url | https://hdl.handle.net/10356/96707 http://hdl.handle.net/10220/13036 |
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