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Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites
Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311950/ https://www.ncbi.nlm.nih.gov/pubmed/32626661 http://dx.doi.org/10.3389/fcimb.2020.00203 |
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author | McPhillie, Martin J. Zhou, Ying Hickman, Mark R. Gordon, James A. Weber, Christopher R. Li, Qigui Lee, Patty J. Amporndanai, Kangsa Johnson, Rachel M. Darby, Heather Woods, Stuart Li, Zhu-hong Priestley, Richard S. Ristroph, Kurt D. Biering, Scott B. El Bissati, Kamal Hwang, Seungmin Hakim, Farida Esaa Dovgin, Sarah M. Lykins, Joseph D. Roberts, Lucy Hargrave, Kerrie Cong, Hua Sinai, Anthony P. Muench, Stephen P. Dubey, Jitender P. Prud'homme, Robert K. Lorenzi, Hernan A. Biagini, Giancarlo A. Moreno, Silvia N. Roberts, Craig W. Antonyuk, Svetlana V. Fishwick, Colin W. G. McLeod, Rima |
author_facet | McPhillie, Martin J. Zhou, Ying Hickman, Mark R. Gordon, James A. Weber, Christopher R. Li, Qigui Lee, Patty J. Amporndanai, Kangsa Johnson, Rachel M. Darby, Heather Woods, Stuart Li, Zhu-hong Priestley, Richard S. Ristroph, Kurt D. Biering, Scott B. El Bissati, Kamal Hwang, Seungmin Hakim, Farida Esaa Dovgin, Sarah M. Lykins, Joseph D. Roberts, Lucy Hargrave, Kerrie Cong, Hua Sinai, Anthony P. Muench, Stephen P. Dubey, Jitender P. Prud'homme, Robert K. Lorenzi, Hernan A. Biagini, Giancarlo A. Moreno, Silvia N. Roberts, Craig W. Antonyuk, Svetlana V. Fishwick, Colin W. G. McLeod, Rima |
author_sort | McPhillie, Martin J. |
collection | PubMed |
description | Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria. |
format | Online Article Text |
id | pubmed-7311950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-73119502020-07-02 Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites McPhillie, Martin J. Zhou, Ying Hickman, Mark R. Gordon, James A. Weber, Christopher R. Li, Qigui Lee, Patty J. Amporndanai, Kangsa Johnson, Rachel M. Darby, Heather Woods, Stuart Li, Zhu-hong Priestley, Richard S. Ristroph, Kurt D. Biering, Scott B. El Bissati, Kamal Hwang, Seungmin Hakim, Farida Esaa Dovgin, Sarah M. Lykins, Joseph D. Roberts, Lucy Hargrave, Kerrie Cong, Hua Sinai, Anthony P. Muench, Stephen P. Dubey, Jitender P. Prud'homme, Robert K. Lorenzi, Hernan A. Biagini, Giancarlo A. Moreno, Silvia N. Roberts, Craig W. Antonyuk, Svetlana V. Fishwick, Colin W. G. McLeod, Rima Front Cell Infect Microbiol Cellular and Infection Microbiology Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria. Frontiers Media S.A. 2020-06-09 /pmc/articles/PMC7311950/ /pubmed/32626661 http://dx.doi.org/10.3389/fcimb.2020.00203 Text en Copyright © 2020 McPhillie, Zhou, Hickman, Gordon, Weber, Li, Lee, Amporndanai, Johnson, Darby, Woods, Li, Priestley, Ristroph, Biering, El Bissati, Hwang, Hakim, Dovgin, Lykins, Roberts, Hargrave, Cong, Sinai, Muench, Dubey, Prud'homme, Lorenzi, Biagini, Moreno, Roberts, Antonyuk, Fishwick and McLeod. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular and Infection Microbiology McPhillie, Martin J. Zhou, Ying Hickman, Mark R. Gordon, James A. Weber, Christopher R. Li, Qigui Lee, Patty J. Amporndanai, Kangsa Johnson, Rachel M. Darby, Heather Woods, Stuart Li, Zhu-hong Priestley, Richard S. Ristroph, Kurt D. Biering, Scott B. El Bissati, Kamal Hwang, Seungmin Hakim, Farida Esaa Dovgin, Sarah M. Lykins, Joseph D. Roberts, Lucy Hargrave, Kerrie Cong, Hua Sinai, Anthony P. Muench, Stephen P. Dubey, Jitender P. Prud'homme, Robert K. Lorenzi, Hernan A. Biagini, Giancarlo A. Moreno, Silvia N. Roberts, Craig W. Antonyuk, Svetlana V. Fishwick, Colin W. G. McLeod, Rima Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites |
title | Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites |
title_full | Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites |
title_fullStr | Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites |
title_full_unstemmed | Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites |
title_short | Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites |
title_sort | potent tetrahydroquinolone eliminates apicomplexan parasites |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311950/ https://www.ncbi.nlm.nih.gov/pubmed/32626661 http://dx.doi.org/10.3389/fcimb.2020.00203 |
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