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Open-source discovery of chemical leads for next-generation chemoprotective antimalarials
To discover leads for next-generation chemoprotective antimalarial drugs,we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1micromola...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516198/ https://www.ncbi.nlm.nih.gov/pubmed/30523084 http://dx.doi.org/10.1126/science.aat9446 |
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author | Antonova-Koch, Yevgeniya Meister, Stephan Abraham, Matthew Luth, Madeline R. Ottilie, Sabine Lukens, Amanda K. Sakata-Kato, Tomoyo Vanaerschot, Manu Owen, Edward Jado, Juan Carlos Maher, Steven P. Calla, Jaeson Plouffe, David Zhong, Yang Chen, Kaisheng Chaumeau, Victor Conway, Amy J. McNamara, Case W. Ibanez, Maureen Gagaring, Kerstin Serrano, Fernando Neria Eribez, Korina Taggard, Cullin McLean Cheung, Andrea L. Lincoln, Christie Ambachew, Biniam Rouillier, Melanie Siegel, Dionicio Nosten, François Kyle, Dennis E. Gamo, Francisco-Javier Zhou, Yingyao Llinás, Manuel Fidock, David A. Wirth, Dyann F. Burrows, Jeremy Campo, Brice Winzeler, Elizabeth A. |
author_facet | Antonova-Koch, Yevgeniya Meister, Stephan Abraham, Matthew Luth, Madeline R. Ottilie, Sabine Lukens, Amanda K. Sakata-Kato, Tomoyo Vanaerschot, Manu Owen, Edward Jado, Juan Carlos Maher, Steven P. Calla, Jaeson Plouffe, David Zhong, Yang Chen, Kaisheng Chaumeau, Victor Conway, Amy J. McNamara, Case W. Ibanez, Maureen Gagaring, Kerstin Serrano, Fernando Neria Eribez, Korina Taggard, Cullin McLean Cheung, Andrea L. Lincoln, Christie Ambachew, Biniam Rouillier, Melanie Siegel, Dionicio Nosten, François Kyle, Dennis E. Gamo, Francisco-Javier Zhou, Yingyao Llinás, Manuel Fidock, David A. Wirth, Dyann F. Burrows, Jeremy Campo, Brice Winzeler, Elizabeth A. |
author_sort | Antonova-Koch, Yevgeniya |
collection | PubMed |
description | To discover leads for next-generation chemoprotective antimalarial drugs,we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1micromolar).Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action. INTRODUCTION: Malaria remains a devastating disease, affecting 216 million people annually, with 445,000 deaths occurring primarily in children under 5 years old. Malaria treatment relies primarily on drugs that target the diseasecausing asexual blood stages (ABS) of Plasmodium parasites, the organisms responsible for human malaria. Whereas travelers may rely on shortterm daily chemoprotective drugs, those living in endemic regions require long-termmalaria protection such as insecticide-treated nets (ITNs) and vector control. However, ITNs do not fully shield individuals from malaria, may lose potency with time, and can be bulky and difficult to use. Another concern is that mosquitosmay become resistant to the active insecticides that are used in ITNs and vector control. RATIONALE: As the possibility of malaria elimination becomesmore tangible, the ideal antimalarial medicine profile should include chemoprotection. Chemoprotectivemedicines typically work against the exoerythrocytic parasite forms that invade and develop in the liver and are responsible for the earliest asymptomatic stage of the infection. Such medicines could be formulated to provide long-acting prophylaxis, safeguarding individuals that are living near or traveling to areas that have been cleared of parasites. Long-acting chemoprotection in endemic regions could also greatly reduce circulating parasite numbersandpotentially replace a vaccine in an elimination campaign. Although millions of compounds have been screened for activity against parasiteABS, and some have been subsequently tested for potential prophylactic activity, large-scale searches that beginwith prophylactic activity have not been performed because of the complexity of the assay: This assay requires the production of infected laboratory-rearedmosquitoes and hand-dissection of the sporozoiteinfected salivary glands frommosquito thoraxes. RESULTS: To discover leads for next-generation chemoprotective antimalarial drugs, we used luciferase-expressing Plasmodium spp. parasites, dissected from more than a million mosquitoes over a 2-year period, to test more than 500,000 compounds for their ability to inhibit liver-stage development of malaria (681 compounds showed a half-maximal inhibitory concentration of<1 µM). Cluster analysis identified potent and previously unreported scaffold families, as well as other series previously associatedwith chemoprophylaxis. These leads were further tested through multiple phenotypic assays that predict stagespecific and multispecies antimalarial activity. This work revealed compound classes that are likely to provide symptomatic relief from bloodstage parasitemia in addition to providing protection. Target identification by use of functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unknownmechanisms of action, somewhichmay disrupt the host pathogen signaling. CONCLUSION: Our data substantially expands the set of compounds with demonstrated activity against two known targets of chemoprotective drugs, cytochrome bc1 and dihydroorotate dehydrogenase. These present a rich collection of chemical diversity that may be exploited by members of the community seeking to accelerate malaria elimination with chemoprotection and chemoprophylaxis through open-source drug discovery. |
format | Online Article Text |
id | pubmed-6516198 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-65161982019-05-24 Open-source discovery of chemical leads for next-generation chemoprotective antimalarials Antonova-Koch, Yevgeniya Meister, Stephan Abraham, Matthew Luth, Madeline R. Ottilie, Sabine Lukens, Amanda K. Sakata-Kato, Tomoyo Vanaerschot, Manu Owen, Edward Jado, Juan Carlos Maher, Steven P. Calla, Jaeson Plouffe, David Zhong, Yang Chen, Kaisheng Chaumeau, Victor Conway, Amy J. McNamara, Case W. Ibanez, Maureen Gagaring, Kerstin Serrano, Fernando Neria Eribez, Korina Taggard, Cullin McLean Cheung, Andrea L. Lincoln, Christie Ambachew, Biniam Rouillier, Melanie Siegel, Dionicio Nosten, François Kyle, Dennis E. Gamo, Francisco-Javier Zhou, Yingyao Llinás, Manuel Fidock, David A. Wirth, Dyann F. Burrows, Jeremy Campo, Brice Winzeler, Elizabeth A. Science Antimalarials To discover leads for next-generation chemoprotective antimalarial drugs,we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1micromolar).Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action. INTRODUCTION: Malaria remains a devastating disease, affecting 216 million people annually, with 445,000 deaths occurring primarily in children under 5 years old. Malaria treatment relies primarily on drugs that target the diseasecausing asexual blood stages (ABS) of Plasmodium parasites, the organisms responsible for human malaria. Whereas travelers may rely on shortterm daily chemoprotective drugs, those living in endemic regions require long-termmalaria protection such as insecticide-treated nets (ITNs) and vector control. However, ITNs do not fully shield individuals from malaria, may lose potency with time, and can be bulky and difficult to use. Another concern is that mosquitosmay become resistant to the active insecticides that are used in ITNs and vector control. RATIONALE: As the possibility of malaria elimination becomesmore tangible, the ideal antimalarial medicine profile should include chemoprotection. Chemoprotectivemedicines typically work against the exoerythrocytic parasite forms that invade and develop in the liver and are responsible for the earliest asymptomatic stage of the infection. Such medicines could be formulated to provide long-acting prophylaxis, safeguarding individuals that are living near or traveling to areas that have been cleared of parasites. Long-acting chemoprotection in endemic regions could also greatly reduce circulating parasite numbersandpotentially replace a vaccine in an elimination campaign. Although millions of compounds have been screened for activity against parasiteABS, and some have been subsequently tested for potential prophylactic activity, large-scale searches that beginwith prophylactic activity have not been performed because of the complexity of the assay: This assay requires the production of infected laboratory-rearedmosquitoes and hand-dissection of the sporozoiteinfected salivary glands frommosquito thoraxes. RESULTS: To discover leads for next-generation chemoprotective antimalarial drugs, we used luciferase-expressing Plasmodium spp. parasites, dissected from more than a million mosquitoes over a 2-year period, to test more than 500,000 compounds for their ability to inhibit liver-stage development of malaria (681 compounds showed a half-maximal inhibitory concentration of<1 µM). Cluster analysis identified potent and previously unreported scaffold families, as well as other series previously associatedwith chemoprophylaxis. These leads were further tested through multiple phenotypic assays that predict stagespecific and multispecies antimalarial activity. This work revealed compound classes that are likely to provide symptomatic relief from bloodstage parasitemia in addition to providing protection. Target identification by use of functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unknownmechanisms of action, somewhichmay disrupt the host pathogen signaling. CONCLUSION: Our data substantially expands the set of compounds with demonstrated activity against two known targets of chemoprotective drugs, cytochrome bc1 and dihydroorotate dehydrogenase. These present a rich collection of chemical diversity that may be exploited by members of the community seeking to accelerate malaria elimination with chemoprotection and chemoprophylaxis through open-source drug discovery. American Association for the Advancement of Science 2018-12-07 2018 /pmc/articles/PMC6516198/ /pubmed/30523084 http://dx.doi.org/10.1126/science.aat9446 Text en 2018 © The Authors, some rights reserved http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Antimalarials Antonova-Koch, Yevgeniya Meister, Stephan Abraham, Matthew Luth, Madeline R. Ottilie, Sabine Lukens, Amanda K. Sakata-Kato, Tomoyo Vanaerschot, Manu Owen, Edward Jado, Juan Carlos Maher, Steven P. Calla, Jaeson Plouffe, David Zhong, Yang Chen, Kaisheng Chaumeau, Victor Conway, Amy J. McNamara, Case W. Ibanez, Maureen Gagaring, Kerstin Serrano, Fernando Neria Eribez, Korina Taggard, Cullin McLean Cheung, Andrea L. Lincoln, Christie Ambachew, Biniam Rouillier, Melanie Siegel, Dionicio Nosten, François Kyle, Dennis E. Gamo, Francisco-Javier Zhou, Yingyao Llinás, Manuel Fidock, David A. Wirth, Dyann F. Burrows, Jeremy Campo, Brice Winzeler, Elizabeth A. Open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
title | Open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
title_full | Open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
title_fullStr | Open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
title_full_unstemmed | Open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
title_short | Open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
title_sort | open-source discovery of chemical leads for next-generation chemoprotective antimalarials |
topic | Antimalarials |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516198/ https://www.ncbi.nlm.nih.gov/pubmed/30523084 http://dx.doi.org/10.1126/science.aat9446 |
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