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标题：Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity
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作者：Florencia Ferraro ; Ileana Corvo ; Lucia Bergalli 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2020
卷号：10
期号：1
页码：1-13
DOI：10.1038/s41598-020-59460-y
出版社：Springer Nature
摘要：Trematode infections such as schistosomiasis and fascioliasis cause significant morbidity in an estimated 250 million people worldwide and the associated agricultural losses are estimated at more than US$ 6 billion per year. Current chemotherapy is limited. Triosephosphate isomerase (TIM), an enzyme of the glycolytic pathway, has emerged as a useful drug target in many parasites, including Fasciola hepatica TIM ( Fh TIM). We identified 21 novel compounds that selectively inhibit this enzyme. Using microscale thermophoresis we explored the interaction between target and compounds and identified a potent interaction between the sulfonyl-1,2,4-thiadiazole (compound 187 ) and Fh TIM, which showed an IC 50 of 5 µM and a K d of 66 nM. In only 4 hours, this compound killed the juvenile form of F. hepatica with an IC 50 of 3 µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of Fh TIM by TCZ, with an IC 50 of 7 µM suggesting a previously uncharacterized role of Fh TIM in the mechanism of action of this drug. Compound 187 was also active against various developmental stages of Schistosoma mansoni . The low toxicity in vitro in different cell types and lack of acute toxicity in mice was demonstrated for this compound, as was demonstrated the efficacy of 187 in vivo in F. hepatica infected mice. Finally, we obtained the first crystal structure of Fh TIM at 1.9 Å resolution which allows us using docking to suggest a mechanism of interaction between compound 187 and TIM. In conclusion, we describe a promising drug candidate to control neglected trematode infections in human and animal health.