Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box.
Chagas disease (CD) is a human disease caused by Trypanosoma cruzi. Whilst endemic in Latin America, the disease is spread around the world due to migration flows, being estimated that 8 million people are infected worldwide and over 10,000 people die yearly of complications linked to CD. Current ch...
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ftdoajarticles:oai:doaj.org/article:940bb37f149343ebab2d086178487f3b 2023-05-15T15:15:16+02:00 Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. Juan Cantizani Pablo Gamallo Ignacio Cotillo Raquel Alvarez-Velilla Julio Martin 2021-07-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009602 https://doaj.org/article/940bb37f149343ebab2d086178487f3b EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009602 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009602 https://doaj.org/article/940bb37f149343ebab2d086178487f3b PLoS Neglected Tropical Diseases, Vol 15, Iss 7, p e0009602 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009602 2022-12-31T15:49:17Z Chagas disease (CD) is a human disease caused by Trypanosoma cruzi. Whilst endemic in Latin America, the disease is spread around the world due to migration flows, being estimated that 8 million people are infected worldwide and over 10,000 people die yearly of complications linked to CD. Current chemotherapeutics is restricted to only two drugs, i.e. benznidazole (BNZ) and nifurtimox (NIF), both being nitroaromatic compounds sharing mechanism of action and exerting suboptimal efficacy and serious adverse effects. Recent clinical trials conducted to reposition antifungal azoles have turned out disappointing due to poor efficacy outcomes despite their promising preclinical profile. This apparent lack of translation from bench models to the clinic raises the question of whether we are using the right in vitro tools for compound selection. We propose that speed of action and cidality, rather than potency, are properties that can differentiate those compounds with better prospect of success to show efficacy in animal models of CD. Here we investigate the use of in vitro assays looking at the kinetics of parasite kill as a valuable surrogate to tell apart slow- (i.e. azoles targeting CYP51) and fast-acting (i.e. nitroaromatic) compounds. Data analysis and experimental design have been optimised to make it amenable for high-throughput compound profiling. Automated data reduction of experimental kinetic points to tabulated curve descriptors in conjunction with PCA, k-means and hierarchical clustering provide drug discoverers with a roadmap to guide navigation from hit qualification of a screening campaign to compound optimisation programs and assessment of combo therapy potential. As an example, we have studied compounds belonging to the GSK Chagas Box stemmed from the HTS campaign run against the full GSK 1.8 million compounds collection [1]. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 7 e0009602 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Juan Cantizani Pablo Gamallo Ignacio Cotillo Raquel Alvarez-Velilla Julio Martin Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Chagas disease (CD) is a human disease caused by Trypanosoma cruzi. Whilst endemic in Latin America, the disease is spread around the world due to migration flows, being estimated that 8 million people are infected worldwide and over 10,000 people die yearly of complications linked to CD. Current chemotherapeutics is restricted to only two drugs, i.e. benznidazole (BNZ) and nifurtimox (NIF), both being nitroaromatic compounds sharing mechanism of action and exerting suboptimal efficacy and serious adverse effects. Recent clinical trials conducted to reposition antifungal azoles have turned out disappointing due to poor efficacy outcomes despite their promising preclinical profile. This apparent lack of translation from bench models to the clinic raises the question of whether we are using the right in vitro tools for compound selection. We propose that speed of action and cidality, rather than potency, are properties that can differentiate those compounds with better prospect of success to show efficacy in animal models of CD. Here we investigate the use of in vitro assays looking at the kinetics of parasite kill as a valuable surrogate to tell apart slow- (i.e. azoles targeting CYP51) and fast-acting (i.e. nitroaromatic) compounds. Data analysis and experimental design have been optimised to make it amenable for high-throughput compound profiling. Automated data reduction of experimental kinetic points to tabulated curve descriptors in conjunction with PCA, k-means and hierarchical clustering provide drug discoverers with a roadmap to guide navigation from hit qualification of a screening campaign to compound optimisation programs and assessment of combo therapy potential. As an example, we have studied compounds belonging to the GSK Chagas Box stemmed from the HTS campaign run against the full GSK 1.8 million compounds collection [1]. |
format |
Article in Journal/Newspaper |
author |
Juan Cantizani Pablo Gamallo Ignacio Cotillo Raquel Alvarez-Velilla Julio Martin |
author_facet |
Juan Cantizani Pablo Gamallo Ignacio Cotillo Raquel Alvarez-Velilla Julio Martin |
author_sort |
Juan Cantizani |
title |
Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. |
title_short |
Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. |
title_full |
Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. |
title_fullStr |
Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. |
title_full_unstemmed |
Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box. |
title_sort |
rate-of-kill (rok) assays to triage large compound sets for chagas disease drug discovery: application to gsk chagas box. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009602 https://doaj.org/article/940bb37f149343ebab2d086178487f3b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 7, p e0009602 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009602 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009602 https://doaj.org/article/940bb37f149343ebab2d086178487f3b |
op_doi |
https://doi.org/10.1371/journal.pntd.0009602 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
7 |
container_start_page |
e0009602 |
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1766345640129855488 |