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; Pavel A. Petukhov

doi:10.1038/s41467-023-39444-y

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

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

14 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 language	English (US)
Article number	3737
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39444-y
State	Published - Dec 2023

ASJC Scopus subject areas

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

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10.1038/s41467-023-39444-y

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Petukhova, V. Z., Aboagye, S. Y., Ardini, M., Lullo, R. P., Fata, F., Byrne, M. E., Gabriele, F., Martin, L. M., Harding, L. N. M., Gone, V., Dangi, B., Lantvit, D. D., Nikolic, D., Ippoliti, R., Effantin, G., Ling, W. L., Johnson, J. J., Thatcher, G. R. J., Angelucci, F., ... Petukhov, P. A. (2023). Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo. Nature communications, 14(1), Article 3737. https://doi.org/10.1038/s41467-023-39444-y

Petukhova, VZ, Aboagye, SY, Ardini, M, Lullo, RP, Fata, F, Byrne, ME, Gabriele, F, Martin, LM, Harding, LNM, Gone, V, Dangi, B, Lantvit, DD, Nikolic, D, Ippoliti, R, Effantin, G, Ling, WL, Johnson, JJ, Thatcher, GRJ, Angelucci, F, Williams, DL & Petukhov, PA 2023, 'Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo', Nature communications, vol. 14, no. 1, 3737. https://doi.org/10.1038/s41467-023-39444-y

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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.",

author = "Petukhova, {Valentina Z.} and Aboagye, {Sammy Y.} and Matteo Ardini and Lullo, {Rachel P.} and Francesca Fata and Byrne, {Margaret E.} and Federica Gabriele and Martin, {Lucy M.} and Harding, {Luke N.M.} and Vamshikrishna Gone and Bikash Dangi and Lantvit, {Daniel D.} and Dejan Nikolic and Rodolfo Ippoliti and Gr{\'e}gory Effantin and Ling, {Wai Li} and Johnson, {Jeremy J.} and Thatcher, {Gregory R.J.} and Francesco Angelucci and Williams, {David L.} and Petukhov, {Pavel A.}",

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AU - Byrne, Margaret E.

AU - Gabriele, Federica

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AU - Harding, Luke N.M.

AU - Gone, Vamshikrishna

AU - Dangi, Bikash

AU - Lantvit, Daniel D.

AU - Nikolic, Dejan

AU - Ippoliti, Rodolfo

AU - Effantin, Grégory

AU - Ling, Wai Li

AU - Johnson, Jeremy J.

AU - Thatcher, Gregory R.J.

AU - Angelucci, Francesco

AU - Williams, David L.

AU - Petukhov, Pavel A.

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

Abstract

ASJC Scopus subject areas

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cryo-EM structure of thioredoxin glutathione reductase in complex with a non-competitive inhibitor

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

Abstract

ASJC Scopus subject areas

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Datasets

cryo-EM structure of thioredoxin glutathione reductase in complex with a non-competitive inhibitor

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