Mechanism of Action of Prethioviridamide, an Anticancer Ribosomally Synthesized and Post-Translationally Modified Peptide with a Polythioamide Structure

ACS Chemical Biology
Shohei TakaseKen Matsumoto

Abstract

Thioviridamide, prethioviridamide, and JBIR-140, which are ribosomally synthesized and post-translationally modified peptides (RiPPs) possessing five thioamide bonds, induce selective apoptosis in various cancer cells, especially those expressing the adenovirus oncogene E1A. However, the target protein of this unique family of bioactive compounds was previously unknown. To investigate the mechanism of action, we adopted a combined approach of genome-wide shRNA library screening, transcriptome profiling, and biochemical identification of prethioviridamide-binding proteins. An shRNA screen identified 63 genes involved in cell sensitivity to prethioviridamide, which included translation initiation factors, aminoacyl tRNA synthetases, and mitochondrial proteins. Transcriptome profiling and subsequent analysis revealed that prethioviridamide induces the integrated stress response (ISR) through the GCN2-ATF4 pathway, which is likely to cause cell death. Furthermore, we found that prethioviridamide binds and inhibits respiratory chain complex V (F1Fo-ATP synthase) in mitochondria, suggesting that inhibition of complex V leads to activation of the GCN2-ATF4 pathway. These results imply that the members of a unique family of RiPPs with ...Continue Reading

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Citations

Aug 23, 2020·International Journal of Molecular Sciences·Luca FrattaruoloAnna Rita Cappello
Sep 18, 2020·European Journal of Medicinal Chemistry·Bhargav A PatelBrian S J Blagg
Feb 12, 2020·Organic Letters·Joshua A Lutz, Carol M Taylor
Nov 24, 2021·Chembiochem : a European Journal of Chemical Biology·Ken Matsumoto, Minoru Yoshida

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