Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

Bernatchez, J. A.; Kil, Y.-S.; Barbosa da Silva, E.; Thomas, D.; McCall, L.-I.; Wendt, K. L.; Souza, J. M.; Ackermann, J.; McKerrow, J. H.; Cichewicz, R. H.; Siqueira-Neto, J. L.

doi:10.1101/2021.05.30.446362

bioRxiv · 10.1101/2021.05.30.446362

Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

Bernatchez, J. A.·Kil, Y.-S.·Barbosa da Silva, E.·Thomas, D.·McCall, L.-I.·Wendt, K. L.·Souza, J. M.·Ackermann, J.·McKerrow, J. H.·Cichewicz, R. H.·Siqueira-Neto, J. L.

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Abstract

Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac and gastrointestinal pathology and caused by the kinetoplastid parasite Trypanosoma cruzi, have yet to be developed. Benznidazole and nifurtimox, which are currently the only available drugs against T. cruzi, are associated with severe adverse effects and questionable efficacy in the late stage of the disease. Natural products have proven to be a rich source of new chemotypes for other infectious agents. We utilized a microscopy-based high-throughput phenotypic screen to identify inhibitors of T. cruzi from a library of natural product samples obtained from fungi procured through a Citizen Science Soil Collection Program (https://whatsinyourbackyard.org/), and the Great Lakes (USA) benthic environment. We identified five leucinostatins (A, B, F, NPDG C and NPDG D) as potent inhibitors of the intracellular amastigote form of T. cruzi. Leucinostatin B also showed in vivo efficacy in a mouse model of Chagas disease. Given prior reports that leucinostatins A and B have antiparasitic activity against the related kinetoplastid T. brucei, our findings suggest a potential cross-trypanocidal compound class and provide a platform for further chemical derivatization of a potent chemical scaffold against T. cruzi.

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Bernatchez, J. A., Kil, Y.-S., Barbosa da Silva, E., Thomas, D., McCall, L.-I., Wendt, K. L., Souza, J. M., Ackermann, J., McKerrow, J. H., Cichewicz, R. H., Siqueira-Neto, J. L.. 2021-05-31. Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi. https://doi.org/10.1101/2021.05.30.446362

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