Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK

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York Biomedical Research Institute, Hull York Medical School, University of York, Wentworth Way, Heslington, York YO10 5DD, UK

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Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA

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York Biomedical Research Institute, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, UK

Author to whom correspondence should be addressed.

Trop. Med. Infect. Dis. 2020, 5(1), 28; https://doi.org/10.3390/tropicalmed5010028

Received: 9 January 2020 / Revised: 11 February 2020 / Accepted: 14 February 2020 / Published: 17 February 2020

(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)

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Abstract

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. View Full-Text

Keywords: sleeping sickness; drug discovery; Trypanosoma growth inhibitors

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MDPI and ACS Style

Rao, S.P.S.; Lakshminarayana, S.B.; Jiricek, J.; Kaiser, M.; Ritchie, R.; Myburgh, E.; Supek, F.; Tuntland, T.; Nagle, A.; Molteni, V.; Mäser, P.; Mottram, J.C.; Barrett, M.P.; Diagana, T.T. Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis. Trop. Med. Infect. Dis. 2020, 5, 28. https://doi.org/10.3390/tropicalmed5010028

AMA Style

Rao SPS, Lakshminarayana SB, Jiricek J, Kaiser M, Ritchie R, Myburgh E, Supek F, Tuntland T, Nagle A, Molteni V, Mäser P, Mottram JC, Barrett MP, Diagana TT. Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis. Tropical Medicine and Infectious Disease. 2020; 5(1):28. https://doi.org/10.3390/tropicalmed5010028

Chicago/Turabian Style

Rao, Srinivasa P.S., Suresh B. Lakshminarayana, Jan Jiricek, Marcel Kaiser, Ryan Ritchie, Elmarie Myburgh, Frantisek Supek, Tove Tuntland, Advait Nagle, Valentina Molteni, Pascal Mäser, Jeremy C. Mottram, Michael P. Barrett, and Thierry T. Diagana. 2020. "Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis" Tropical Medicine and Infectious Disease 5, no. 1: 28. https://doi.org/10.3390/tropicalmed5010028

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Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

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