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

  • Nat Commun. 2023 Jun 22;14(1):3737. doi: 10.1038/s41467-023-39444-y.
Valentina Z Petukhova  #  1 ,  Sammy Y Aboagye  #  2 ,  Matteo Ardini  #  3 ,  Rachel P Lullo  2 ,  Francesca Fata  3 ,  Margaret E Byrne  2 ,  Federica Gabriele  3 ,  Lucy M Martin  2 ,  Luke N M Harding  1 ,  Vamshikrishna Gone  4 ,  Bikash Dangi  5 ,  Daniel D Lantvit  4 ,  Dejan Nikolic  1 ,  Rodolfo Ippoliti  3 ,  Grégory Effantin  6 ,  Wai Li Ling  6 ,  Jeremy J Johnson  5 ,  Gregory R J Thatcher  7 ,  Francesco Angelucci  8 ,  David L Williams  9 ,  Pavel A Petukhov  10
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
  • 2. Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL, USA.
  • 3. Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy.
  • 4. UICentre, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
  • 5. Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
  • 6. University of Grenoble Alpes, CEA, CNRS, IBS, F-38000, Grenoble, France.
  • 7. Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ, USA.
  • 8. Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy. [email protected].
  • 9. Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, IL, USA. [email protected].
  • 10. Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 37349300 DOI: 10.1038/s41467-023-39444-y
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.

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