Frontiers in Cellular and Infection Microbiology (Jun 2020)
Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites
- Martin J. McPhillie,
- Ying Zhou,
- Mark R. Hickman,
- James A. Gordon,
- Christopher R. Weber,
- Qigui Li,
- Patty J. Lee,
- Kangsa Amporndanai,
- Rachel M. Johnson,
- Heather Darby,
- Stuart Woods,
- Zhu-hong Li,
- Richard S. Priestley,
- Kurt D. Ristroph,
- Scott B. Biering,
- Kamal El Bissati,
- Seungmin Hwang,
- Farida Esaa Hakim,
- Sarah M. Dovgin,
- Joseph D. Lykins,
- Lucy Roberts,
- Kerrie Hargrave,
- Hua Cong,
- Anthony P. Sinai,
- Stephen P. Muench,
- Jitender P. Dubey,
- Robert K. Prud'homme,
- Hernan A. Lorenzi,
- Giancarlo A. Biagini,
- Silvia N. Moreno,
- Craig W. Roberts,
- Svetlana V. Antonyuk,
- Colin W. G. Fishwick,
- Rima McLeod,
- Rima McLeod
Affiliations
- Martin J. McPhillie
- School of Chemistry, The University of Leeds, Leeds, United Kingdom
- Ying Zhou
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL, United States
- Mark R. Hickman
- Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States
- James A. Gordon
- School of Chemistry, The University of Leeds, Leeds, United Kingdom
- Christopher R. Weber
- Department of Pathology, The University of Chicago, Chicago, IL, United States
- Qigui Li
- Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States
- Patty J. Lee
- Experimental Therapeutics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States
- Kangsa Amporndanai
- Department of Biochemistry and Systems Biology, Faculty of Health and Life Sciences, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, Liverpool, United Kingdom
- Rachel M. Johnson
- School of Biomedical Sciences, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, The University of Leeds, Leeds, United Kingdom
- Heather Darby
- School of Chemistry, The University of Leeds, Leeds, United Kingdom
- Stuart Woods
- Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, Glasgow, United Kingdom
- Zhu-hong Li
- Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Richard S. Priestley
- Department of Tropical Disease Biology, Research Center for Drugs and Diagnostics, The Liverpool School of Tropical Medicine, Liverpool, United Kingdom
- Kurt D. Ristroph
- 0Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United States
- Scott B. Biering
- Department of Pathology, The University of Chicago, Chicago, IL, United States
- Kamal El Bissati
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL, United States
- Seungmin Hwang
- Department of Pathology, The University of Chicago, Chicago, IL, United States
- Farida Esaa Hakim
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL, United States
- Sarah M. Dovgin
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL, United States
- Joseph D. Lykins
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL, United States
- Lucy Roberts
- Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, Glasgow, United Kingdom
- Kerrie Hargrave
- Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, Glasgow, United Kingdom
- Hua Cong
- School of Chemistry, The University of Leeds, Leeds, United Kingdom
- Anthony P. Sinai
- 1Microbiology, Immunology and Molecular Genetics, The University of Kentucky College of Medicine, Lexington, KY, United States
- Stephen P. Muench
- School of Biomedical Sciences, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, The University of Leeds, Leeds, United Kingdom
- Jitender P. Dubey
- 2Animal Parasitic Diseases Laboratory (APDL), USDA-ARS, Beltsville, MD, United States
- Robert K. Prud'homme
- 0Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, United States
- Hernan A. Lorenzi
- 3Department of Infectious Diseases, J Craig Venter Institute, Rockville, MD, United States
- Giancarlo A. Biagini
- Department of Tropical Disease Biology, Research Center for Drugs and Diagnostics, The Liverpool School of Tropical Medicine, Liverpool, United Kingdom
- Silvia N. Moreno
- Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, United States
- Craig W. Roberts
- Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, Glasgow, United Kingdom
- Svetlana V. Antonyuk
- Department of Biochemistry and Systems Biology, Faculty of Health and Life Sciences, Institute of Systems, Molecular and Integrative Biology, The University of Liverpool, Liverpool, United Kingdom
- Colin W. G. Fishwick
- School of Chemistry, The University of Leeds, Leeds, United Kingdom
- Rima McLeod
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL, United States
- Rima McLeod
- 4Department of Pediatrics (Infectious Diseases), Institute of Genomics, Genetics, and Systems Biology, Global Health Center, Toxoplasmosis Center, CHeSS, The College, University of Chicago, Chicago, IL, United States
- DOI
- https://doi.org/10.3389/fcimb.2020.00203
- Journal volume & issue
-
Vol. 10
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 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.
Keywords
- Toxoplasma gondii
- Plasmodium falciparum
- cytochrome bc1
- tetrahydroquinolone
- nanoformulation
- structure-guided design
