EMD-15084
cryo-EM structure of thioredoxin glutathione reductase in complex with a non-competitive inhibitor
EMD-15084
Single-particle3.6 Å
Deposition: 01/06/2022Map released: 14/06/2023
Last modified: 13/11/2024
Sample Organism:
Schistosoma mansoni
Sample: TGR in complex with an inhibitor
Fitted models: 8a1r (Avg. Q-score: 0.312)
Deposition Authors: Ardini M
,
Angelucci F ,
Fata F ,
Gabriele F,
Effantin G ,
Ling W,
Williams DL ,
Petukhova VZ,
Petukhov PA
Sample: TGR in complex with an inhibitor
Fitted models: 8a1r (Avg. Q-score: 0.312)
Deposition Authors: Ardini M
,
Angelucci F ,
Fata F ,
Gabriele F,
Effantin G ,
Ling W,
Williams DL ,
Petukhova VZ,
Petukhov PA
Non-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo.
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) Nat Commun , 14 , 3737 - 3737
,
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) Nat Commun , 14 , 3737 - 3737
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 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.