학술논문
Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo
Document Type
Original Paper
Author
Petukhova, Valentina Z.; Aboagye, Sammy Y.; Ardini, Matteo; Lullo, Rachel P.; Fata, Francesca; Byrne, Margaret E.; Gabriele, Federica; Martin, Lucy M.; Harding, Luke N. M.; Gone, Vamshikrishna; Dangi, Bikash; Lantvit, Daniel D.; Nikolic, Dejan; Ippoliti, Rodolfo; Effantin, Grégory; Ling, Wai Li; Johnson, Jeremy J.; Thatcher, Gregory R. J.; Angelucci, Francesco; Williams, David L.; Petukhov, Pavel A.
Source
Nature Communications. 14(1)
Subject
Language
English
ISSN
2041-1723
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.
Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.
Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.