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. Williams

Pavel A. Petukhov

Institute for Environment and Sanitation Studies

University of Illinois at Chicago
University of L'Aquila
Rush University Medical Center
Université Grenoble Alpes
University of Arizona

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

24 Citations (Scopus)

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
Article number	3737
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-39444-y
Publication status	Published - Dec 2023

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SDG 3 Good Health and Well-being

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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

@article{d84ce8940a8b4ce38bd3146067e719d0,

title = "Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo",

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.\}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-39444-y",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

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number = "1",

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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

TY - JOUR

T1 - Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo

AU - Petukhova, Valentina Z.

AU - Aboagye, Sammy Y.

AU - Ardini, Matteo

AU - Lullo, Rachel P.

AU - Fata, Francesca

AU - Byrne, Margaret E.

AU - Gabriele, Federica

AU - Martin, Lucy M.

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.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85162770375

U2 - 10.1038/s41467-023-39444-y

DO - 10.1038/s41467-023-39444-y

M3 - Article

C2 - 37349300

AN - SCOPUS:85162770375

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3737

ER -

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

Abstract

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