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.
|Journal||Frontiers in Cellular and Infection Microbiology|
|State||Published - Jun 9 2020|
Bibliographical noteFunding Information:
We thank and gratefully also acknowledge the support of the Cornwell Mann family, the Rodriguez, Musillami, Quinn, Rosenthal, Greenberg, Morel, Rooney and Engel families, Taking out Toxo, and The Toxoplasmosis Research Institute. We would like to thank beamline scientists at Proxima2, Synchrotron Soeil, France, Proposal 20161037 and iNEXT (Proposal 1728) for Financial support for synchrotron access. We thank Abigail Spedding and Nisha Pokar for their assistance in helping JG at Leeds University with compound synthesis, and Ryan Gonciarz (‘RG’) for his compound RG38. We also acknowledge the assistance of Leon Wang, Ph.D of Princeton University with size determination for the final step of nanoformulation for this proof of principle study. Dennis Steindler kindly provided the primary human brain neuronal stem cells used in this study. Funding. This work was supported by NIAID NIH DMID U01 AI082180 (RM) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant #5T35DK062719-28 to FH. This was also supported by National Institutes of Health (NIH) contract number HHNS272200900007C, NIH. National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID) award numbers R01AI071319(NIAID) and R01AI027530 (NIAID) (RM); NIAID contract Number HHNS272200900007C; NIAID award number U19AI110819 (HL): NIAID award number U01 AI077887(NIAID) and Defense Threat Reduction Agency award number 13-C-0055, and Department of Defense award numbers W911NF-09-D0001 and W911SR-07-C0101(MH). This work was also supported by R01 AI128356 to SNM. The work also was supported by the Bill and Melinda Gates Foundation (BMGF, OPP1150755) (RKP). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship under Grant No. #DGE-1656466 awarded to KR. RJ was funded by a Ph.D scholarship by the Wellcome Trust (109158/B/15/Z).
© 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.
- Plasmodium falciparum
- Toxoplasma gondii
- cytochrome bc1
- structure-guided design
ASJC Scopus subject areas
- Microbiology (medical)
- Infectious Diseases