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Can Allostery Be a Key Strategy for Targeting PTP1B in Drug Discovery? A Lesson from Trodusquemine

Rosanna Maccari1, Rosaria Ottanà1

  • 1Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.

International Journal of Molecular Sciences
|June 10, 2023
PubMed

Insights

Trodusquemine, a natural aminosterol, shows promise as an allosteric inhibitor of Protein Tyrosine Phosphatase 1B (PTP1B). This enzyme

Area of Science:

  • Biochemistry and Molecular Biology
  • Pharmacology
  • Drug Discovery

Background:

  • Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme in signaling pathways linked to obesity, diabetes, cancer, and neurodegeneration.
  • Inhibiting PTP1B offers a therapeutic strategy for these pathologies.
  • Allosteric inhibition presents an advantage over catalytic site-directed inhibition for PTP1B drug development.

Purpose of the Study:

  • To review the therapeutic potential of trodusquemine as an allosteric PTP1B inhibitor.
  • To explore the correlation between trodusquemine's activities and PTP1B inhibition.
  • To examine aminosterol analogues and structure-activity relationships for novel PTP1B inhibitor discovery.

Main Methods:

  • Literature review of preclinical and clinical studies on trodusquemine.
  • Analysis of trodusquemine's mechanism of action as a non-competitive PTP1B inhibitor.
  • Examination of structure-activity relationships of related aminosterol compounds.

Main Results:

  • Trodusquemine, a natural aminosterol, acts as a non-competitive inhibitor of PTP1B.
  • Trodusquemine exhibits diverse therapeutic effects, including antidiabetic, anti-obesity, anti-cancer, and neuroprotective properties.
  • These activities are linked to its PTP1B inhibitory function.

Conclusions:

  • Trodusquemine is a significant milestone in the development of allosteric PTP1B inhibitors.
  • Its broad therapeutic potential warrants further investigation for various human diseases.
  • Aminosterol analogues offer a promising avenue for discovering new PTP1B-targeting drugs.
Keywords:
MSI-1436allosteric inhibitioncancerdiabetesdrug discoveryneurodegenerative diseasesobesityprotein tyrosine phosphatase 1Bstructure–activity relationshipstrodusquemine

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