Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex

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Abstract

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A∙GTP∙aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.

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Jordan D Carelli

Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Steven G Sethofer

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Geoffrey A Smith

Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
Howard R Miller

Novartis Institutes for BioMedical Research, Cambridge, United States

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The authors declare that no competing interests exist.
Jillian L Simard

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
William C Merrick

Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, United States

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The authors declare that no competing interests exist.
Rishi K Jain

Novartis Institutes for BioMedical Research, Cambridge, United States

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The authors declare that no competing interests exist.
Nathan T Ross

Novartis Institutes for BioMedical Research, Cambridge, United States

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The authors declare that no competing interests exist.
Jack Taunton

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States

For correspondence
jack.taunton@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

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