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

Srinivasa P S Rao,Tove Tuntland,Ryan Ritchie,Elmarie Myburgh,Suresh B Lakshminarayana,Frantisek Supek,Marcel Kaiser,Michael P Barrett,Advait Nagle,Jeremy C Mottram,Pascal Mäser,Thierry T Diagana,Valentina Molteni,Jan Jiricek

doi:10.3390/tropicalmed5010028

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.

Highlights

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)
Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense
We described our efforts to identify novel chemotypes for the treatment of HAT. These efforts led the identification of GNF6702, a prototypical pan-kinetoplastid inhibitor that was efficacious in the mouse models for all three kinetoplastid diseases [8]

Summary

Introduction

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasites Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. The successful introduction of nifurtimox–eflornithine combination therapy (NECT) for the treatment of gambiense HAT significantly helped in achieving a cure in stage 2 HAT patients [2]. The introduction of fexinidazole, as an oral drug capable of curing stage 1 and stage 2 disease, offers great potential, and a further orally available drug, acoziborole, is currently being evaluated in late-stage clinical trials [3]. Recent publications showing that trypanosomes dwell in adipose tissue [5] and skin [6], along with several reports of possible animal reservoirs of gambiense trypanosomes and latent human infections, all point out potential threats to the elimination of HAT [7]

Methods

Results

Conclusion