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

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 kinetoplast...

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Autores principales: Rao, Srinivasa P S, Lakshminarayana, Suresh B, Jiricek, Jan, Kaiser, Marcel, Ritchie, Ryan, Myburgh, Elmarie, Supek, Frantisek, Tuntland, Tove, Nagle, Advait, Molteni, Valentina, Mäser, Pascal, Mottram, Jeremy C, Barrett, Michael P, Diagana, Thierry T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157554/
https://www.ncbi.nlm.nih.gov/pubmed/32079320
http://dx.doi.org/10.3390/tropicalmed5010028
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author Rao, Srinivasa P S
Lakshminarayana, Suresh B
Jiricek, Jan
Kaiser, Marcel
Ritchie, Ryan
Myburgh, Elmarie
Supek, Frantisek
Tuntland, Tove
Nagle, Advait
Molteni, Valentina
Mäser, Pascal
Mottram, Jeremy C
Barrett, Michael P
Diagana, Thierry T
author_facet Rao, Srinivasa P S
Lakshminarayana, Suresh B
Jiricek, Jan
Kaiser, Marcel
Ritchie, Ryan
Myburgh, Elmarie
Supek, Frantisek
Tuntland, Tove
Nagle, Advait
Molteni, Valentina
Mäser, Pascal
Mottram, Jeremy C
Barrett, Michael P
Diagana, Thierry T
author_sort Rao, Srinivasa P S
collection PubMed
description 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.
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spelling pubmed-71575542020-05-01 Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis Rao, Srinivasa P S Lakshminarayana, Suresh B Jiricek, Jan Kaiser, Marcel Ritchie, Ryan Myburgh, Elmarie Supek, Frantisek Tuntland, Tove Nagle, Advait Molteni, Valentina Mäser, Pascal Mottram, Jeremy C Barrett, Michael P Diagana, Thierry T Trop Med Infect Dis Article 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. MDPI 2020-02-17 /pmc/articles/PMC7157554/ /pubmed/32079320 http://dx.doi.org/10.3390/tropicalmed5010028 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rao, Srinivasa P S
Lakshminarayana, Suresh B
Jiricek, Jan
Kaiser, Marcel
Ritchie, Ryan
Myburgh, Elmarie
Supek, Frantisek
Tuntland, Tove
Nagle, Advait
Molteni, Valentina
Mäser, Pascal
Mottram, Jeremy C
Barrett, Michael P
Diagana, Thierry T
Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
title Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
title_full Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
title_fullStr Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
title_full_unstemmed Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
title_short Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
title_sort anti-trypanosomal proteasome inhibitors cure hemolymphatic and meningoencephalic murine infection models of african trypanosomiasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157554/
https://www.ncbi.nlm.nih.gov/pubmed/32079320
http://dx.doi.org/10.3390/tropicalmed5010028
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