Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

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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 et al (show 24 more authors) , 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 ORCID: 0000-0002-2779-9946, Fishwick, Colin WG and McLeod, Rima (2020) Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. Frontiers in Cellular and Infection Microbiology, 10. 203-.

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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 <i>b</i> inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces <i>Toxoplasma gondii</i> tachyzoites and encysted bradyzoites <i>in vitro</i>, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant <i>Plasmodium falciparum in vitro</i>. Causal prophylaxis and radical cure are achieved after <i>P. berghei</i> 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.

Item Type:	Article
Uncontrolled Keywords:	Toxoplasma gondii, Plasmodium falciparum, cytochrome bc1, tetrahydroquinolone, nanoformulation, structure-guided design, transcriptomics, RPS13 Delta
Depositing User:	Symplectic Admin
Date Deposited:	12 Jun 2020 07:41
Last Modified:	18 Jan 2023 23:49
DOI:	10.3389/fcimb.2020.00203
Open Access URL:	https://doi.org/10.3389/fcimb.2020.00203
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3090126

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• Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. (deposited 10 Jun 2020 07:50)
  • Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. (deposited 12 Jun 2020 07:41) [Currently Displayed]