Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.

Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exp...

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Autores principales:	Nina Svensen, Susan Wyllie, David W Gray, Manu De Rycker
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/0428e734a42f4d65a9fe295ff74ee419
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spelling	oai:doaj.org-article:0428e734a42f4d65a9fe295ff74ee4192021-11-25T06:33:24ZLive-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.1935-27271935-273510.1371/journal.pntd.0009870https://doaj.org/article/0428e734a42f4d65a9fe295ff74ee4192021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pntd.0009870https://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exposing a lack of understanding of how to translate laboratory findings to the clinic. Following these failures many new model systems have been developed, both in vitro and in vivo, that provide improved understanding of the causes for clinical trial failures. Amongst these are in vitro rate-of-kill (RoK) assays that reveal how fast compounds kill intracellular parasites. Such assays have shown clear distinctions between the compounds that failed in clinical trials and the standard of care. However, the published RoK assays have some key drawbacks, including low time-resolution and inability to track the same cell population over time. Here, we present a new, live-imaging RoK assay for intracellular T. cruzi that overcomes these issues. We show that the assay is highly reproducible and report high time-resolution RoK data for key clinical compounds as well as new chemical entities. The data generated by this assay allow fast acting compounds to be prioritised for progression, the fate of individual parasites to be tracked, shifts of mode-of-action within series to be monitored, better PKPD modelling and selection of suitable partners for combination therapy.Nina SvensenSusan WyllieDavid W GrayManu De RyckerPublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 10, p e0009870 (2021)
institution	DOAJ
collection	DOAJ
language	EN
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 Nina Svensen Susan Wyllie David W Gray Manu De Rycker Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.
description	Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exposing a lack of understanding of how to translate laboratory findings to the clinic. Following these failures many new model systems have been developed, both in vitro and in vivo, that provide improved understanding of the causes for clinical trial failures. Amongst these are in vitro rate-of-kill (RoK) assays that reveal how fast compounds kill intracellular parasites. Such assays have shown clear distinctions between the compounds that failed in clinical trials and the standard of care. However, the published RoK assays have some key drawbacks, including low time-resolution and inability to track the same cell population over time. Here, we present a new, live-imaging RoK assay for intracellular T. cruzi that overcomes these issues. We show that the assay is highly reproducible and report high time-resolution RoK data for key clinical compounds as well as new chemical entities. The data generated by this assay allow fast acting compounds to be prioritised for progression, the fate of individual parasites to be tracked, shifts of mode-of-action within series to be monitored, better PKPD modelling and selection of suitable partners for combination therapy.
format	article
author	Nina Svensen Susan Wyllie David W Gray Manu De Rycker
author_facet	Nina Svensen Susan Wyllie David W Gray Manu De Rycker
author_sort	Nina Svensen
title	Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.
title_short	Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.
title_full	Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.
title_fullStr	Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.
title_full_unstemmed	Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.
title_sort	live-imaging rate-of-kill compound profiling for chagas disease drug discovery with a new automated high-content assay.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/0428e734a42f4d65a9fe295ff74ee419
work_keys_str_mv	AT ninasvensen liveimagingrateofkillcompoundprofilingforchagasdiseasedrugdiscoverywithanewautomatedhighcontentassay AT susanwyllie liveimagingrateofkillcompoundprofilingforchagasdiseasedrugdiscoverywithanewautomatedhighcontentassay AT davidwgray liveimagingrateofkillcompoundprofilingforchagasdiseasedrugdiscoverywithanewautomatedhighcontentassay AT manuderycker liveimagingrateofkillcompoundprofilingforchagasdiseasedrugdiscoverywithanewautomatedhighcontentassay
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Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay.

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