Using functional signature ontology (FUSION) to identify mechanisms of action for Natural products

Malia B. Potts, Hyun Seok Kim, Kurt W. Fisher, Youcai Hu, Yazmin P. Carrasco, Gamze Betul Bulut, Yi Hung Ou, Mireya L. Herrera-Herrera, Federico Cubillos, Saurabh Mendiratta, Guanghua Xiao, Matan Hofree, Trey Ideker, Yang Xie, Lily Jun Shen Huang, Robert E. Lewis, John B. MacMillan, Michael A. White

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA (miRNA) libraries. With this strategy, we matched proteins and miRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected siRNAs, miRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets.

Original languageEnglish (US)
Article numberra90
JournalScience signaling
Volume6
Issue number297
DOIs
StatePublished - Oct 15 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Potts, M. B., Kim, H. S., Fisher, K. W., Hu, Y., Carrasco, Y. P., Bulut, G. B., Ou, Y. H., Herrera-Herrera, M. L., Cubillos, F., Mendiratta, S., Xiao, G., Hofree, M., Ideker, T., Xie, Y., Huang, L. J. S., Lewis, R. E., MacMillan, J. B., & White, M. A. (2013). Using functional signature ontology (FUSION) to identify mechanisms of action for Natural products. Science signaling, 6(297), [ra90]. https://doi.org/10.1126/scisignal.2004657