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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #373476

Research Project: Detection and Control of Foodborne Parasites for Food Safety

Location: Animal Parasitic Diseases Laboratory

Title: Potent tetrahydroquinolone eliminates apicomplexan parasites

item MCPHILLIE, MARTIN - University Of Leeds
item ZHOU, YING - University Of Chicago
item HICKMAN, MARK - Walter Reed Army Institute
item GORDON, JAMES - University Of Leeds
item WEBER R., CHRISTOPHER - University Of Chicago
item LI, QIGUI - Walter Reed Army Institute
item LEE, PATTY - Walter Reed Army Institute
item AMPORNDANAI, KANGSA - University Of Liverpool
item JOHNSON, RACHEL - University Of Leeds
item DARBY, HEATHER - University Of Leeds
item WOODS, STUART - University Of Strathclyde
item LI, ZHUHONG - University Of Georgia
item PRIESTLEY, RICHSRD S. - Liverpool School Of Tropical Medicine
item RISTROPH, KURT - Princeton University
item BIERING, SCOTT - University Of Chicago
item EL BISSATI, KAMAL - University Of Chicago
item HWANG, SEUNGMIN - University Of Chicago
item HAKIM, FARIDA - University Of Kentucky
item DOVGIN, SARAH - University Of Chicago
item LYKINS, JOSEPH - University Of Chicago
item ROBERTS, LUCY - University Of Strathclyde
item HARGRAVE, KERRIE - University Of Strathclyde
item CONG, HUA - University Of Chicago
item SINAI, ANTHONY - US Department Of Agriculture (USDA)
item MUENCH, STEPHEN - University Of Leeds
item Dubey, Jitender
item PRID'HOMME, ROBERT - Princeton University
item LORENZI, HERNAN - University Of Chicago
item BIAGINI, GIANCARLO - Liverpool School Of Tropical Medicine
item MORENO, SILVIA - University Of Georgia
item ROBERTS, CRAIG - University Of Strathclyde
item ATONYUK, SVETLANA - University Of Liverpool
item FISHWICK, COLIN - University Of Leeds
item MCLEOD, RIMA - University Of Chicago

Submitted to: Frontiers in Cellular and Infection Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/16/2020
Publication Date: 6/9/2020
Citation: Mcphillie, M., Zhou, Y., Hickman, M., Gordon, J., Weber R., C., Li, Q., Lee, P., Amporndanai, K., Johnson, R., Darby, H., Woods, S., Li, Z., Priestley, R.S., Ristroph, K., Biering, S.B., El Bissati, K., Hwang, S., Hakim, F.E., Dovgin, S., Lykins, J.D., Roberts, L., Hargrave, K., Cong, H., Sinai, A.P., Muench, S.P., Dubey, J.P., Prid'Homme, R., Lorenzi, H.A., Biagini, G.A., Moreno, S.N., Roberts, C.W., Atonyuk, S., Fishwick, C., Mcleod, R. 2020. Potent tetrahydroquinolone eliminates apicomplexan parasites. Frontiers in Cellular and Infection Microbiology. 203:10.

Interpretive Summary: Apicomplexans are a group of single celled parasites affecting humans and livestock. Apicomplexans include important genera including Plasmodium (cause of malaria in humans), Eimeria (cause of coccidiosis in livestock and poultry), Neospora (cause of abortion in livestock) and Toxoplasma that cause clinical toxoplasmosis in humans and animals. There are very few effective drugs that cure these diseases. In the present paper, authors report on a next generation anti-apicomplexan lead compound,40 JAG21, a tetrahydroquinolone, with curative activity against Toxoplasma and Plasmodium. The discovery of this broad-spectrum medicine will be of interest to biologists, pharmacologists, veterinarians, and parasitologists. This study was completed in 2018, before the termination of Toxoplasma project at USDA.

Technical 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 cytochromeb 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 infections in vivo. 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 (2.5mg/kg) or three days treatment at reduced dose (0.625mg/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.