Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.
Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two a...
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ftdoajarticles:oai:doaj.org/article:a0849e17ea374980b5b31bd21097f609 2023-05-15T15:10:31+02:00 Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. Juan Carlos Pizarro Tanya Hills Guillermo Senisterra Amy K Wernimont Claire Mackenzie Neil R Norcross Michael A J Ferguson Paul G Wyatt Ian H Gilbert Raymond Hui 2013-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002492 https://doaj.org/article/a0849e17ea374980b5b31bd21097f609 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3798429?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002492 https://doaj.org/article/a0849e17ea374980b5b31bd21097f609 PLoS Neglected Tropical Diseases, Vol 7, Iss 10, p e2492 (2013) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2013 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002492 2022-12-31T16:20:56Z Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 7 10 e2492 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Juan Carlos Pizarro Tanya Hills Guillermo Senisterra Amy K Wernimont Claire Mackenzie Neil R Norcross Michael A J Ferguson Paul G Wyatt Ian H Gilbert Raymond Hui Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite. |
format |
Article in Journal/Newspaper |
author |
Juan Carlos Pizarro Tanya Hills Guillermo Senisterra Amy K Wernimont Claire Mackenzie Neil R Norcross Michael A J Ferguson Paul G Wyatt Ian H Gilbert Raymond Hui |
author_facet |
Juan Carlos Pizarro Tanya Hills Guillermo Senisterra Amy K Wernimont Claire Mackenzie Neil R Norcross Michael A J Ferguson Paul G Wyatt Ian H Gilbert Raymond Hui |
author_sort |
Juan Carlos Pizarro |
title |
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. |
title_short |
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. |
title_full |
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. |
title_fullStr |
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. |
title_full_unstemmed |
Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design. |
title_sort |
exploring the trypanosoma brucei hsp83 potential as a target for structure guided drug design. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2013 |
url |
https://doi.org/10.1371/journal.pntd.0002492 https://doaj.org/article/a0849e17ea374980b5b31bd21097f609 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 7, Iss 10, p e2492 (2013) |
op_relation |
http://europepmc.org/articles/PMC3798429?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002492 https://doaj.org/article/a0849e17ea374980b5b31bd21097f609 |
op_doi |
https://doi.org/10.1371/journal.pntd.0002492 |
container_title |
PLoS Neglected Tropical Diseases |
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7 |
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10 |
container_start_page |
e2492 |
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