Anti-trypanosomal proteasome inhibitors cure hemolymphatic and meningoencephalic murine infection models of african trypanosomiasis

Rao, Srinivasa P. S. and Lakshminarayana, Suresh B. and Jiricek, Jan and Kaiser, Marcel and Ritchie, Ryan and Myburgh, Elmarie and Supek, Frantisek and Tuntland, Tove and Nagle, Advait and Molteni, Valentina and Mäser, Pascal and Mottram, Jeremy C. and Barrett, Michael P. and Diagana, Thierry T.. (2020) Anti-trypanosomal proteasome inhibitors cure hemolymphatic and meningoencephalic murine infection models of african trypanosomiasis. Tropical medicine and infectious disease, 5. p. 28.

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Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and 'easy to use' oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against; Trypanosoma brucei rhodesiense; and; Trypanosoma brucei gambiense; strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in; T. brucei; . These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Kaiser, Marcel and Mäser, Pascal
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Multidisciplinary Digital Publishing Institute
Note:Publication type according to Uni Basel Research Database: Journal article
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edoc DOI:
Last Modified:05 Mar 2020 13:12
Deposited On:05 Mar 2020 13:12

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