McPhillie, MJ orcid.org/0000-0001-8264-8211, Zhou, Y, Hickman, MR et al. (31 more authors) (2020) Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. Frontiers in Cellular and Infection Microbiology, 10. 203. ISSN 2235-2988
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 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. 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. |
Keywords: | Toxoplasma gondii, Plasmodium falciparum, cytochrome bc1, tetrahydroquinolone, nanoformulation, structure-guided design, transcriptomics, RPS131 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Aug 2020 12:47 |
Last Modified: | 25 Jun 2023 22:20 |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fcimb.2020.00203 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:163025 |