Organic Chemistry

Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA-Virus-Inhibitors

Authors

  • Patrick Haack Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research ,
  • Kirsten Harmrolfs Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research ,
  • Chantal Bader Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research ,
  • Ronald Garcia Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research ,
  • Antonia Gunesch Institute of Experimental Virology - TWINCORE & Centre for Experimental and Clinical Infection Research & German Center for Infection Research & Cluster of Excellence RESIST ,
  • Sibylle Haid Institute of Experimental Virology - TWINCORE & Centre for Experimental and Clinical Infection Research & German Center for Infection Research & Cluster of Excellence RESIST ,
  • Alexander Popoff Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research ,
  • Alexander Voltz Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research ,
  • Heeyoung Kim Heidelberg University & German Center for Infection Research & German Cancer Research Center ,
  • Ralf Bartenschlager Heidelberg University & German Center for Infection Research & German Cancer Research Center ,
  • Thomas Pietschmann Institute of Experimental Virology - TWINCORE & Centre for Experimental and Clinical Infection Research & German Center for Infection Research & Cluster of Excellence RESIST ,
  • Rolf Müller Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Saarland University & German Center for Infection Research

Abstract

During our search for novel myxobacterial natural products, we discovered the Thiamyxins: thiazole- and thiazoline-rich non-ribosomal peptide-polyketide hybrids with potent antiviral activity. We isolated two cyclized and two open-chain congeners of this unprecedented natural product family, whereof the non-cyclized Thiamyxin D was found to be fused to a glycerol unit attached to the C-terminal carboxyl function. Alongside their structure elucidation and absolute stereochemistry, we present the biosynthetic origin of the Thiamyxins supported by a concise biosynthesis model based on biosynthetic gene cluster analysis and feeding experiments with isotope labelled precursors. We report an unprecedented incorporation of a 2-(hydroxymethyl)-4-methylpent-3-enoic acid moiety originating from the involved polyketide synthase featuring a rare GCN5-related N-acetyltransferase-like decarboxylase domain. The Thiamyxins showed potent inhibition of different RNA-viruses as analysed in cell culture models of corona, zika and dengue virus infection. Their potency up to a half maximal inhibitory concentration of 560 nM combined with milder cytotoxic effects on human cell lines indicate a potential for further development of the Thiamyxins as broad-spectrum antivirals targeting RNA-viruses.

Content

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Supplementary material

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Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA-Virus-Inhibitors - Supporting Information
We describe the microbiological and analytical methodology used for the preparation, analysis and purification of the Thiamyxins. We also report details on the bioinformatics analysis performed to investigate their biosynthetic origin, as well as NMR raw data and details about the biological assays.