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Streamlined Methods for Profiling Targeted Michael Acceptor Molecules Reveal Natural PTP1B Covalent Inhibitors.

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Summary

Natural products contain Michael acceptor molecules (MAMs) that covalently bind to proteins. Andrographis paniculata extract, particularly oridonin, inhibits protein tyrosine phosphatase 1B (PTP1B), impacting insulin signaling and glucose metabolism.

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Area of Science:

  • Natural Products Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Michael acceptor molecules (MAMs) in natural products are reactive electrophiles.
  • MAMs can form covalent bonds with protein targets, making them valuable for drug development.

Purpose of the Study:

  • To develop a workflow for profiling MAMs in natural products.
  • To investigate covalent interactions between MAMs and protein targets.
  • To identify MAMs in Andrographis paniculata extract that inhibit protein tyrosine phosphatase 1B (PTP1B).

Main Methods:

  • Methoxypolyethylene glycol maleimide (mPEG) tag-shift technique for target identification.
  • Thiocholine iodide (TCI) labeling and mass spectrometry for MAM discovery.
  • Enzyme activity assays and cell-based assays to assess PTP1B inhibition and downstream effects.

Main Results:

  • Andrographis paniculata extract covalently inhibits PTP1B.
  • Oridonin was identified as the key compound modifying PTP1B.
  • Oridonin covalently binds to Cys92 and Cys215 of PTP1B, inhibiting its activity.
  • Oridonin treatment enhanced insulin signaling (IRβ, Akt, ERK phosphorylation) and glucose uptake.
  • TCI labeling and mPEG tag-shift are effective for MAM discovery and target identification.

Conclusions:

  • Oridonin is a potent covalent inhibitor of PTP1B with significant implications for insulin signaling and glucose metabolism.
  • The developed workflow, including TCI labeling and mPEG tag-shift, is valuable for covalent drug discovery.
  • This study provides new insights into the therapeutic potential of oridonin and natural product-derived MAMs.