Large-scale transcriptome mining enables macrocyclic diversification and improved bioactivity of the stephanotic acid scaffold

Xiaofeng Wang, Khadija Shafiq, Derrick A. Ousley, Desnor N. Chigumba, Dulciana Davis, Kali M. McDonough, Lisa S. Mydy, Jonathan Z. Sexton and Roland D. Kersten ()
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Xiaofeng Wang: University of Michigan
Khadija Shafiq: University of Michigan
Derrick A. Ousley: University of Michigan
Desnor N. Chigumba: University of Michigan
Dulciana Davis: University of Michigan
Kali M. McDonough: University of Michigan
Lisa S. Mydy: University of Michigan
Jonathan Z. Sexton: University of Michigan
Roland D. Kersten: University of Michigan

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Nearly 10,000 plant species are represented by RNA-seq datasets in the NCBI sequence read archive, which are difficult to search in unassembled format due to database size. Here, we optimize RNA-seq assembly to transform most of this public RNA-seq data to a searchable database for biosynthetic gene discovery. We test our transcriptome mining pipeline towards the diversification of moroidins, which are plant ribosomally-synthesized and posttranslationally-modified peptides (RiPPs) biosynthesized from copper-dependent peptide cyclases. Moroidins are bicyclic compounds with a conserved stephanotic acid scaffold, which becomes cytotoxic to non-small cell lung adenocarcinoma cells with an additional C-terminal macrocycle. We discover moroidin analogs with second ring structures diversified at the crosslink and the non-crosslinked residues including a moroidin analog from water chickweed, which exhibits higher cytotoxicity against lung adenocarcinoma cells than moroidin. Our study expands stephanotic acid-type peptides to grasses, Lowiaceae, mints, pinks, and spurges while demonstrating that large-scale transcriptome mining can broaden the medicinal chemistry toolbox for chemical and biological exploration of eukaryotic RiPP lead structures.

Date: 2025
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DOI: 10.1038/s41467-025-59428-4

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