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Instruments / Technical Area	Publication Details	Published	Actions
I24-Microfocus Macromolecular Crystallography	New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections Martin Mcphillie , Ying Zhou , Kamal El Bissati , Jitender Dubey , Hernan Lorenzi , Michael Capper , Amanda K. Lukens , Mark Hickman , Stephen Muench , Shiv Kumar Verma , Christopher R. Weber , Kelsey Wheeler , James Gordon , Justin Sanders , Hong Moulton , Kai Wang , Taek-kyun Kim , Yuqing He , Tatiana Santos , Stuart Woods , Patty Lee , David Donkin , Eric Kim , Laura Fraczek , Joseph Lykins , Farida Esaa , Fatima Alibana-clouser , Sarah Dovgin , Louis Weiss , Gael Brasseur , Dyann Wirth , Michael Kent , Leroy Hood , Brigitte Meunieur , Craig W. Roberts , S. Samar Hasnain , Svetlana V. Antonyuk , Colin Fishwick , Rima Mcleod Scientific Reports 6 DOI: 10.1038/srep29179 Diamond Proposal Number(s): [11740] Open Access Show Abstract ▼ Abstract: Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.	Jul 2016

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I24-Microfocus Macromolecular Crystallography

New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections