PUBLICATION

Integrated Compound Profiling Screens Identify the Mitochondrial Electron Transport Chain as the Molecular Target of the Natural Products Manassantin, Sesquicillin, and Arctigenin

Authors
Lai, K., Selinger, D.W., Solomon, J.M., Wu, H., Schmitt, E., Serluca, F.C., Curtis, D., and Benson, J.D.
ID
ZDB-PUB-121127-8
Date
2013
Source
ACS Chemical Biology   8(1): 257-267 (Journal)
Registered Authors
Serluca, Fabrizio
Keywords
none
MeSH Terms
  • Animals
  • Dose-Response Relationship, Drug
  • Electron Transport Chain Complex Proteins/drug effects*
  • Furans/chemistry
  • Furans/pharmacology*
  • Gene Expression Profiling
  • Lignans/chemistry
  • Lignans/pharmacology*
  • Mitochondrial Membranes/drug effects*
  • Molecular Structure
  • Naphthalenes/chemistry
  • Naphthalenes/pharmacology*
  • Zebrafish
PubMed
23138533 Full text @ ACS Chem. Biol.
Abstract

Phenotypic compound screens can be used to identify novel targets in signaling pathways and disease processes, but the usefulness of these screens depends on the ability to quickly determine the target and mechanism of action of the molecules identified as hits. One fast route to discovering the mechanism of action of a compound is to profile its properties and to match this profile with those of compounds of known mechanism of action. In this work, the Novartis collection of over 12,000 pure natural products was screened for effects on early zebrafish development. The largest phenotypic class of hits, which caused developmental arrest without necrosis, contained known electron transport chain inhibitors and many compounds of unknown mechanism of action. High-throughput transcriptional profiling revealed that these compounds are mechanistically related to one another. Metabolic and biochemical assays confirmed that all of the molecules that induced developmental arrest without necrosis inhibited the electron transport chain. These experiments demonstrate that the electron transport chain is the target of the natural products manassantin, sesquicillin, and arctigenin. The overlap between the zebrafish and transcriptional profiling screens was not perfect, indicating that multiple profiling screens are necessary to fully characterize molecules of unknown function. Together, zebrafish screening and transcriptional profiling represent sensitive and scalable approaches for identifying bioactive compounds and elucidating their mechanism of action.

Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping