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Spirocyclic β-lactone secondary metabolites modulate spliceosome function.

Kathryn E Penton1, Sydney A Bates1, Hannah L Thirman2,3,4

  • 1Department of Chemistry, Vanderbilt University, Nashville, TN 37232.

Proceedings of the National Academy of Sciences of the United States of America
|March 31, 2026
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Summary
This summary is machine-generated.

Spirocyclic β-lactones (SβLs) from Streptomyces platensis show potent cytotoxicity by targeting the spliceosome. These natural products offer a new therapeutic avenue for cancers reliant on alternative RNA splicing.

Keywords:
alternative splicingfunctional metabolomicsnatural product discoveryspliceosomethermal proteome profiling

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Area of Science:

  • Natural Product Chemistry
  • Molecular Pharmacology
  • Cancer Biology

Background:

  • Spirocyclic β-lactones (SβLs) are cytotoxic natural products with an unknown mechanism of action.
  • Actinomycetota, specifically Streptomyces platensis, produce SβLs via cryptic gene clusters.

Purpose of the Study:

  • To elucidate the mechanism of action of SβLs.
  • To discover new SβLs and characterize their structure-activity relationships.
  • To explore the therapeutic potential of SβLs in cancer.

Main Methods:

  • Isolation and structure elucidation of SβLs from Streptomyces platensis.
  • Single cell Multiplexed Activity Metabolomics to assess cell death markers.
  • Cytotoxicity assays and phospho-flow cytometry for structure-activity relationship analysis.
  • Global cellular thermal proteome profiling and alternative splicing analysis.

Main Results:

  • Several SβLs, including a new variant, were isolated and correlated with a cryptic biosynthetic gene cluster for oxazolomycin D (OxD) family metabolites.
  • SβLs possess two pharmacophores: a polyketide component for target engagement and a β-lactone warhead for cytotoxicity.
  • OxD treatment strongly interacted with and modulated spliceosome-associated proteins, leading to functional changes in RNA splicing.
  • Phosphoprotein-S6 phosphorylation inhibition was observed, indicating a specific cellular response.

Conclusions:

  • Spirocyclic β-lactones exhibit dual pharmacophores, contributing to their potent cytotoxicity and target engagement.
  • Oxazolomycin D and related SβLs modulate the spliceosome, impacting RNA splicing.
  • The spliceosome-associated cellular response to OxD presents a novel therapeutic opportunity for cancers with aberrant RNA splicing.