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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7157554 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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