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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
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Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

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ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A

Joseph Tillotson1, Magdalena Kedzior1, Larissa Guimarães2

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, P.O. Box 210207, Tuscon, AZ 85721, United States.

Bioorganic & Medicinal Chemistry Letters
|August 1, 2017
PubMed

Insights

Marine natural products elisabatin A and allolaurinterol inhibit eukaryotic initiation factor 4A (eIF4A) ATPase activity. These compounds show cytotoxicity against cancer cells, with allolaurinterol also potently inhibiting eIF4A helicase activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Marine Natural Products Chemistry

Background:

  • Cancer cells exhibit activated translation initiation, crucial for proliferation.
  • The eukaryotic initiation factor 4F (eIF4F) complex, particularly the eIF4A helicase, is a rate-limiting step and a potential therapeutic target.

Purpose of the Study:

  • To discover novel inhibitors of eIF4A ATPase activity from natural product libraries.
  • To evaluate the biochemical and cellular effects of identified compounds.

Main Methods:

  • Biochemical ATPase activity screen of marine and terrestrial natural products.
  • Enzymological analyses to determine inhibition kinetics (ATP-competitive).
  • Cytotoxicity assays against A549 (lung) and MDA-MA-468 (breast) cancer cell lines.
  • Assessment of eIF4A helicase activity inhibition.

Main Results:

  • Identified elisabatin A and allolaurinterol from marine sources with low µM inhibition of eIF4A ATPase activity.
  • Both compounds demonstrated ATP-competitive inhibition.
  • Compounds showed moderate cytotoxicity against tested cancer cell lines.
  • Allolaurinterol exhibited potent inhibition of eIF4A helicase activity, correlating with ATPase inhibition.

Conclusions:

  • Elisabatin A and allolaurinterol are promising marine-derived inhibitors of eIF4A.
  • Allolaurinterol's dual inhibition of ATPase and helicase activities makes it a strong candidate for further anticancer drug development targeting translation initiation.
Keywords:
CancerDEAD box helicaseInhibitorNatural productsTranslationeIF4A

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