Mechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors
Meehan, Michael J.
Dorrestein, Pieter C.
Moore, Bradley S.
Online Publication Date2015-03-05
Print Publication Date2015-08
Permanent link to this recordhttp://hdl.handle.net/10754/346717
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AbstractThalassospiramides 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 α,β-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 α,β-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.
CitationMechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors 2015, 5:8783 Scientific Reports
SponsorsThe authors thank Dr. Jianwei Sun for discussions regarding the structural chemistry, Dr. Peggy Pai, Miss Xiaofen Liu and Miss Joyce Wong for technical assistance with the MALDI-TOF-MS, Dr. Daniela B.B. Trivella for 20S proteasome inhibition assay, and HKUST Biosciences Central Research Facility for providing MS services. The work was supported by grants from the China Ocean Mineral Resources Research and Development Association (DY125-15-T-02), the King Abdullah University of Science and Technology (SA-C0040/UK-C0016), the National Natural Science Foundation of China (21273188), and the NIH (GM97509).
PubMed Central IDPMC4350077
CollectionsPublications Acknowledging KAUST Support
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