Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity

Florencia Ferraro , Ileana Corvo , Lucia Bergalli , Andrea Ilarraz , Mauricio Cabrera , Jorge Gil , Brian Susuki , Conor R Caffrey (1) , David Timson , Xavier Robert (2) , Christophe Guillon (2) , Teresa Freire (3) , Guzman Alvarez (4)

1 Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego]
2 MMSB - Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry
3 Departamento de inmunobiologia, Facultad de Medicina [Montevideo]
4 CENUR Litoral Norte

Trematode infections such as schistosomiasis and fascioliasis cause signifcant 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 identifed 21 novel compounds that selectively inhibit this enzyme. Using microscale thermophoresis we explored the interaction between target and compounds and identifed a potent interaction between the sulfonyl-1,2,4-thiadiazole (compound 187) and FhTIM, which showed an IC50 of 5µM and a Kd of 66nM. In only 4hours, this compound killed the juvenile form of F. hepatica with an IC50 of 3µM, better than the reference drug triclabendazole (TCZ). Interestingly, we discovered in vitro inhibition of FhTIM by TCZ, with an IC50 of 7µM 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 diferent cell types and lack of acute toxicity in mice was demonstrated for this compound, as was demonstrated the efcacy of 187 in vivo in F. hepatica infected mice. Finally, we obtained the frst crystal structure of FhTIM at 1.9Å 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.

Domaines: Sciences du Vivant [q-bio]; Biologie structurale [q-bio.BM]; Parasitologie

Florencia Ferraro, Ileana Corvo, Lucia Bergalli, Andrea Ilarraz, Mauricio Cabrera, et al.. Novel and selective inactivators of Triosephosphate isomerase with anti-trematode activity. Scientific Reports, 2020, 10 (1), ⟨10.1038/s41598-020-59460-y⟩. ⟨hal-02571943⟩