Anti-Trypanosomal proteasome inhibitors cure hemolymphatic and meningoencephalic murine infection models of African Trypanosomiasis

Rao, S. P.S. et al. (2020) Anti-Trypanosomal proteasome inhibitors cure hemolymphatic and meningoencephalic murine infection models of African Trypanosomiasis. Tropical Medicine and Infectious Disease, 5(1), 28. (doi: 10.3390/tropicalmed5010028)

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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.

Item Type:Articles
Additional Information:Funding: This research was funded by Wellcome Trust, United Kingdom, grant number WT-103024MA and WT-104976. (This article belongs to the Special Issue Human African Trypanosomiasis (HAT, Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges).
Keywords:sleeping sickness, drug discovery, Trypanosoma growth inhibitors.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ritchie, Mr Ryan and Myburgh, Dr Elmarie and Barrett, Professor Michael and Mottram, Professor Jeremy
Creator Roles:
Mottram, J.Conceptualization, Data curation, Funding acquisition, Project administration, Supervision, Writing – review and editing
Barrett, M.Conceptualization, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing
Myburgh, E.Data curation, Formal analysis, Methodology, Resources, Supervision, Writing – review and editing
Ritchie, R.Formal analysis, Methodology
Authors: 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., and Diagana, T. T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Tropical Medicine and Infectious Disease
Publisher:MDPI
ISSN:2414-6366
ISSN (Online):2414-6366
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Tropical Medicine and Infectious Disease 5(1):28
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190800In vivo screening resource to support drug development in parasitic diseaseJeremy MottramWellcome Trust (WELLCOTR)104976/Z14/ZIII - Parasitology