Mechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors

Handle URI:
http://hdl.handle.net/10754/346717
Title:
Mechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors
Authors:
Lu, Liang; Meehan, Michael J.; Gu, Shuo; Chen, Zhilong; Zhang, Weipeng; Zhang, Gen; Liu, Lingli; Huang, Xuhui; Dorrestein, Pieter C.; Xu, Ying; Moore, Bradley S.; Qian, Pei-Yuan
Abstract:
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 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.
Citation:
Mechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors 2015, 5:8783 Scientific Reports
Publisher:
Nature Publishing Group
Journal:
Scientific Reports
KAUST Grant Number:
SA-C0040; UK-C0016
Issue Date:
5-Mar-2015
DOI:
10.1038/srep08783
PubMed ID:
25740631
PubMed Central ID:
PMC4350077
Type:
Article
ISSN:
2045-2322
Sponsors:
The 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).
Additional Links:
http://www.nature.com/doifinder/10.1038/srep08783
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorLu, Liangen
dc.contributor.authorMeehan, Michael J.en
dc.contributor.authorGu, Shuoen
dc.contributor.authorChen, Zhilongen
dc.contributor.authorZhang, Weipengen
dc.contributor.authorZhang, Genen
dc.contributor.authorLiu, Linglien
dc.contributor.authorHuang, Xuhuien
dc.contributor.authorDorrestein, Pieter C.en
dc.contributor.authorXu, Yingen
dc.contributor.authorMoore, Bradley S.en
dc.contributor.authorQian, Pei-Yuanen
dc.date.accessioned2015-03-16T10:58:46Zen
dc.date.available2015-03-16T10:58:46Zen
dc.date.issued2015-03-05en
dc.identifier.citationMechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitors 2015, 5:8783 Scientific Reportsen
dc.identifier.issn2045-2322en
dc.identifier.pmid25740631en
dc.identifier.doi10.1038/srep08783en
dc.identifier.urihttp://hdl.handle.net/10754/346717en
dc.description.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.en
dc.description.sponsorshipThe 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).en
dc.publisherNature Publishing Groupen
dc.relation.urlhttp://www.nature.com/doifinder/10.1038/srep08783en
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en
dc.titleMechanism of Action of Thalassospiramides, A New Class of Calpain Inhibitorsen
dc.typeArticleen
dc.identifier.journalScientific Reportsen
dc.identifier.pmcidPMC4350077en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDivision of Life Science, School of Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Chinaen
dc.contributor.institutionSkaggs School of Pharmacy & Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92037, United Statesen
dc.contributor.institutionDepartment of Chemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Chinaen
dc.contributor.institutionDepartment of Pharmacology, University of California at San Diego, La Jolla, California 92037, United Statesen
dc.contributor.institutionCenter for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92037, United Statesen
dc.contributor.institutionSchool of Life Science, Shenzhen University, Nanhai Ave 3688, Shenzhen, Guangdong Province, 518060, Chinaen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.grant.numberSA-C0040en
kaust.grant.numberUK-C0016en
kaust.grant.programKAUST Global Collaborative Research Programen

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