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

Author

Listed:
  • Liqing Hu

    (Virginia Commonwealth University
    Central South University
    Hunan Normal University)

  • Cancan Sun

    (Virginia Commonwealth University)

  • Justin M. Kidd

    (Virginia Commonwealth University)

  • Jizhong Han

    (Shenzhen Bay Laboratory)

  • Xianjun Fang

    (Virginia Commonwealth University)

  • Hongtao Li

    (Virginia Commonwealth University)

  • Qingdai Liu

    (Tianjin University of Science & Technology)

  • Aaron E. May

    (Virginia Commonwealth University)

  • Qianbin Li

    (Central South University)

  • Lei Zhou

    (Shenzhen Bay Laboratory)

  • Qinglian Liu

    (Virginia Commonwealth University)

Abstract

Proteins of the Hsp110 family are molecular chaperones that play important roles in protein homeostasis in eukaryotes. The pathogenic fungus Candida albicans, which causes infections in humans, has a single Hsp110, termed Msi3. Here, we provide proof-of-principle evidence supporting fungal Hsp110s as targets for the development of new antifungal drugs. We identify a pyrazolo[3,4-b] pyridine derivative, termed HLQ2H (or 2H), that inhibits the biochemical and chaperone activities of Msi3, as well as the growth and viability of C. albicans. Moreover, the fungicidal activity of 2H correlates with its inhibition of in vivo protein folding. We propose 2H and related compounds as promising leads for development of new antifungals and as pharmacological tools for the study of the molecular mechanisms and functions of Hsp110s.

Suggested Citation

  • Liqing Hu & Cancan Sun & Justin M. Kidd & Jizhong Han & Xianjun Fang & Hongtao Li & Qingdai Liu & Aaron E. May & Qianbin Li & Lei Zhou & Qinglian Liu, 2023. "A first-in-class inhibitor of Hsp110 molecular chaperones of pathogenic fungi," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38220-2
    DOI: 10.1038/s41467-023-38220-2
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    References listed on IDEAS

    as
    1. Vasant Muralidharan & Anna Oksman & Priya Pal & Susan Lindquist & Daniel E. Goldberg, 2012. "Plasmodium falciparum heat shock protein 110 stabilizes the asparagine repeat-rich parasite proteome during malarial fevers," Nature Communications, Nature, vol. 3(1), pages 1-10, January.
    2. Luke Whitesell & Nicole Robbins & David S. Huang & Catherine A. McLellan & Tanvi Shekhar-Guturja & Emmanuelle V. LeBlanc & Catherine S. Nation & Raymond Hui & Ashley Hutchinson & Cathy Collins & Shara, 2019. "Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    3. Alexander Rosenberg & Iuliana V. Ene & Maayan Bibi & Shiri Zakin & Ella Shtifman Segal & Naomi Ziv & Alon M. Dahan & Arnaldo Lopes Colombo & Richard J. Bennett & Judith Berman, 2018. "Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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