Mechanism of action of thalassospiramides, a new class of calpain inhibitors

Scientific Reports
Liang LuPei-Yuan Qian

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.

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Citations

Jul 28, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Katarzyna StarskaMagdalena Bryś
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Mar 16, 2017·Natural Product Reports·John W BluntMichèle R Prinsep

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Methods Mentioned

BETA
NMR
chemical modifications
PCR
Assay

Software Mentioned

GROMACS
AutoDock Tools ( ADT )
AutoDock Vina
AutoDock

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