期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep08783
关键词
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资金
- China Ocean Mineral Resources Research and Development Association [DY125-15-T-02]
- King Abdullah University of Science and Technology [SA-C0040/UK-C0016]
- National Natural Science Foundation of China [21273188]
- NIH [GM97509]
Thalassospiramides comprise a large family of lipopeptide natural products produced by Thalassospira and Tistrella marine bacteria. Here we provide further evidence of their nanomolar inhibitory activity against the human calpain 1 protease. Analysis of structure-activity relationship data supported our hypothesis that the rigid 12-membered ring containing an alpha,beta-unsaturated carbonyl moiety is the pharmacologically active functional group, in contrast to classic electrophilic warheads in known calpain inhibitors. Using a combination of chemical modifications, mass spectrometric techniques, site-directed mutagenesis, and molecular modeling, we show the covalent binding of thalassospiramide's alpha,beta-unsaturated carbonyl moiety to the thiol group of calpain's catalytic Cys115 residue by a Michael 1,4-addition reaction. As nanomolar calpain inhibitors with promising selectivity and low toxicity from natural sources are rare, we consider thalassospiramides as promising drug leads.
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