6R8H

Triosephosphate isomerase from liver fluke (Fasciola hepatica).

6R8H の概要

• エントリーDOI: 10.2210/pdb6r8h/pdb
• 分子名称: Triosephosphate isomerase, SULFATE ION (3 entities in total)
• 機能のキーワード: triose phosphate isomerase; fasciola hepatica; tim;, isomerase
• 由来する生物種: Fasciola hepatica (Liver fluke)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 165446.56

構造登録者

Ferraro, F.,Corvo, I.,Bergalli, L.,Ilarraz, A.,Cabrera, M.,Gil, J.,Susuki, B.,Caffrey, C.,Timson, D.J.,Robert, X.,Guillon, C.,Alvarez, G. (登録日: 2019-04-01, 公開日: 2020-02-12, 最終更新日: 2024-01-24)

主引用文献

Ferraro, F.,Corvo, I.,Bergalli, L.,Ilarraz, A.,Cabrera, M.,Gil, J.,Susuki, B.M.,Caffrey, C.R.,Timson, D.J.,Robert, X.,Guillon, C.,Freire, T.,Alvarez, G.
Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity.
Sci Rep, 10:2587-2587, 2020

PubMed Abstract: 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 (FhTIM). 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 FhTIM, which showed an IC of 5 µM and a K of 66 nM. In only 4 hours, this compound killed the juvenile form of F. hepatica with an IC of 3 µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of FhTIM by TCZ, with an IC of 7 µM suggesting a previously uncharacterized role of FhTIM 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 FhTIM 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.

PubMed: 32054976
DOI: 10.1038/s41598-020-59460-y

実験手法

X-RAY DIFFRACTION (1.9 Å)