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Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo

Author

Listed:
  • Valentina Z. Petukhova

    (University of Illinois at Chicago)

  • Sammy Y. Aboagye

    (Rush University Medical Center)

  • Matteo Ardini

    (University of L’Aquila)

  • Rachel P. Lullo

    (Rush University Medical Center)

  • Francesca Fata

    (University of L’Aquila)

  • Margaret E. Byrne

    (Rush University Medical Center)

  • Federica Gabriele

    (University of L’Aquila)

  • Lucy M. Martin

    (Rush University Medical Center)

  • Luke N. M. Harding

    (University of Illinois at Chicago)

  • Vamshikrishna Gone

    (University of Illinois at Chicago)

  • Bikash Dangi

    (University of Illinois at Chicago)

  • Daniel D. Lantvit

    (University of Illinois at Chicago)

  • Dejan Nikolic

    (University of Illinois at Chicago)

  • Rodolfo Ippoliti

    (University of L’Aquila)

  • Grégory Effantin

    (University of Grenoble Alpes, CEA, CNRS, IBS)

  • Wai Li Ling

    (University of Grenoble Alpes, CEA, CNRS, IBS)

  • Jeremy J. Johnson

    (University of Illinois at Chicago)

  • Gregory R. J. Thatcher

    (University of Arizona)

  • Francesco Angelucci

    (University of L’Aquila)

  • David L. Williams

    (Rush University Medical Center)

  • Pavel A. Petukhov

    (University of Illinois at Chicago)

Abstract

Only praziquantel is available for treating schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs suggest that resistance is evolving in the field. Thioredoxin glutathione reductase (TGR) is essential for schistosome survival and a validated drug target. TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects. In this work, we identify noncovalent TGR inhibitors with efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO. Comparisons with previous in vivo studies with praziquantel suggests that these inhibitors outperform the drug of choice for schistosomiasis against juvenile worms.

Suggested Citation

  • Valentina Z. Petukhova & Sammy Y. Aboagye & Matteo Ardini & Rachel P. Lullo & Francesca Fata & Margaret E. Byrne & Federica Gabriele & Lucy M. Martin & Luke N. M. Harding & Vamshikrishna Gone & Bikash, 2023. "Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39444-y
    DOI: 10.1038/s41467-023-39444-y
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    References listed on IDEAS

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    1. Sergey Yegorov & Vineet Joag & Ronald M. Galiwango & Sara V. Good & Juliet Mpendo & Egbert Tannich & Andrea K. Boggild & Noah Kiwanuka & Bernard S. Bagaya & Rupert Kaul, 2019. "Schistosoma mansoni treatment reduces HIV entry into cervical CD4+ T cells and induces IFN-I pathways," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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