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Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts

J. Stone Doggett, Tracey Schultz, Alyssa J. Miller, View ORCID ProfileIgor Bruzual, Sovitj Pou, Rolf Winter, Rozalia Dodean, Lev N. Zakharov, Aaron Nilsen, Michael K Riscoe, Vern B Carruthers
doi: https://doi.org/10.1101/2020.03.19.999664
J. Stone Doggett
aDivision of Infectious Diseases, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA
bDepartment of Hospital and Specialty Medicine, Veterans Administration Portland Healthcare System, Portland, OR 97239, USA
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  • For correspondence: doggettj@ohsu.edu
Tracey Schultz
cDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Alyssa J. Miller
dProgram in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
eDepartment of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
fInstitute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
gPenn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Igor Bruzual
bDepartment of Hospital and Specialty Medicine, Veterans Administration Portland Healthcare System, Portland, OR 97239, USA
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  • ORCID record for Igor Bruzual
Sovitj Pou
bDepartment of Hospital and Specialty Medicine, Veterans Administration Portland Healthcare System, Portland, OR 97239, USA
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Rolf Winter
bDepartment of Hospital and Specialty Medicine, Veterans Administration Portland Healthcare System, Portland, OR 97239, USA
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Rozalia Dodean
bDepartment of Hospital and Specialty Medicine, Veterans Administration Portland Healthcare System, Portland, OR 97239, USA
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Lev N. Zakharov
hDepartment of Chemistry, University of Oregon, Eugene, OR 97403, USA
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Aaron Nilsen
aDivision of Infectious Diseases, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA
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Michael K Riscoe
aDivision of Infectious Diseases, Oregon Health & Science University School of Medicine, Portland, OR 97239, USA
bDepartment of Hospital and Specialty Medicine, Veterans Administration Portland Healthcare System, Portland, OR 97239, USA
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Vern B Carruthers
cDepartment of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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Abstract

Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines for toxoplasmosis have high rates of adverse effects that interfere with therapeutic and prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors of Toxoplasma gondii proliferation in vitro and in animal models of acute and latent infection. ELQ-316, in particular, was found to be effective orally against acute toxoplasmosis in mice and highly selective for the T. gondii cytochrome b over the human cytochrome b. Despite oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a six-fold increase in both Cmax (maximum plasma concentration) and AUC (area under the curve) of ELQ-316. The increased bioavailability of ELQ-316, when administered as ELQ-334, resulted in greater efficacy than the equivalent dose of ELQ-316 against acute toxoplasmosis and had similar efficacy against latent toxoplasmosis compared to intraperitoneal administration of ELQ-316. Carbonate ester prodrugs are a successful strategy to overcome the limited oral bioavailability of ELQs for the treatment of toxoplasmosis.

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Posted March 20, 2020.
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Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
J. Stone Doggett, Tracey Schultz, Alyssa J. Miller, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia Dodean, Lev N. Zakharov, Aaron Nilsen, Michael K Riscoe, Vern B Carruthers
bioRxiv 2020.03.19.999664; doi: https://doi.org/10.1101/2020.03.19.999664
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Orally Bioavailable Endochin-like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
J. Stone Doggett, Tracey Schultz, Alyssa J. Miller, Igor Bruzual, Sovitj Pou, Rolf Winter, Rozalia Dodean, Lev N. Zakharov, Aaron Nilsen, Michael K Riscoe, Vern B Carruthers
bioRxiv 2020.03.19.999664; doi: https://doi.org/10.1101/2020.03.19.999664

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