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

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 Dangi, Daniel D. Lantvit, Dejan Nikolic, Rodolfo Ippoliti, Grégory Effantin, Wai Li Ling, Jeremy J. Johnson, Gregory R.J. Thatcher, Francesco Angelucci, David L. WilliamsPavel A. Petukhov

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Article number3737
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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