Thiamyxins: Structure and Biosynthesis of Myxobacterial RNA-Virus Inhibitors
Haack P, Harmrolfs K, Bader C, Garcia R, Gunesch A, Haid S, Popoff A, Voltz A, Kim H, Bartenschlager R, Pietschmann T, Müller R
Published in
Angewandte Chemie (international Ed. In English): Volume 61, Issue 52, Page e202212946
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 four congeners of this unprecedented natural product family with the non-cyclized thiamyxin D fused to a glycerol unit at the C-terminus. Alongside their structure elucidation, we present a concise biosynthesis model based on biosynthetic gene cluster analysis and isotopically labelled precursor feeding. We report incorporation of a 2-(hydroxymethyl)-4-methylpent-3-enoic acid moiety by a GCN5-related N-acetyltransferase-like decarboxylase domain featuring polyketide synthase. The thiamyxins show potent inhibition of RNA viruses 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 the potential for further development of the thiamyxins.
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