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. Williams () and Pavel A. Petukhov ()
Additional contact information
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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39444-y

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