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A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi

Liqing Hu1,2,3, Cancan Sun1, Justin M Kidd1

  • 1Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.

Nature Communications
|May 12, 2023
PubMed

Insights

A novel compound, HLQ2H, targets the Msi3 protein in Candida albicans, inhibiting its chaperone activity and fungal growth. This discovery offers a new strategy for developing antifungal drugs.

Area of Science:

  • Molecular Biology
  • Mycology
  • Pharmacology

Background:

  • Hsp110 proteins are crucial molecular chaperones for maintaining protein homeostasis in eukaryotes.
  • Candida albicans, a human pathogenic fungus, possesses a unique Hsp110 protein known as Msi3.
  • Fungal Hsp110s represent a potential target for novel antifungal drug development.

Purpose of the Study:

  • To investigate fungal Hsp110s as potential targets for new antifungal therapies.
  • To identify and characterize inhibitors of Msi3, the Hsp110 of Candida albicans.
  • To explore the therapeutic potential of identified inhibitors against fungal infections.

Main Methods:

  • Biochemical assays to assess Msi3 inhibition.
  • Chaperone activity assays for Msi3.
  • Fungal growth and viability assays for Candida albicans.
  • In vivo protein folding inhibition studies.

Main Results:

  • A pyrazolo[3,4-b] pyridine derivative, HLQ2H (2H), was identified as an inhibitor of Msi3.
  • HLQ2H effectively inhibits the biochemical and chaperone activities of Msi3.
  • 2H demonstrates fungicidal activity against Candida albicans by inhibiting in vivo protein folding.

Conclusions:

  • Fungal Hsp110s, specifically Msi3, are validated as drug targets for antifungal development.
  • HLQ2H and related compounds show promise as lead candidates for new antifungal agents.
  • These compounds can also serve as valuable pharmacological tools for studying Hsp110 functions.

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