title: Identification of ML251, a Potent Inhibitor of T. brucei and T. cruzi Phosphofructokinase.
abstract: Human African Trypanosomiasis (HAT) is a severe, often fatal disease caused by the parasitic protist Trypanosoma brucei. The glycolytic pathway has been identified as the sole mechanism for ATP generation in the infective stage of these organisms, and several glycolytic enzymes, phosphofructokinase (PFK) in particular, have shown promise as potential drug targets. Herein, we describe the discovery of ML251, a novel nanomolar inhibitor of T. brucei PFK, and the structure-activity relationships within the series.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh , Michael Swann Building, The King's Buildings, Mayfield Road, Edinburgh EH9 3JR, U.K.
authors.forename: Montserrat G
authors.initials: MG
authors.lastname: Vásquez-Valdivieso
authors.affiliation: Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh , Michael Swann Building, The King's Buildings, Mayfield Road, Edinburgh EH9 3JR, U.K.
authors.forename: Hugh P
authors.initials: HP
authors.lastname: Morgan
authors.affiliation: Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh , Michael Swann Building, The King's Buildings, Mayfield Road, Edinburgh EH9 3JR, U.K.
authors.forename: Iain
authors.initials: I
authors.lastname: McNae
authors.affiliation: Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh , Michael Swann Building, The King's Buildings, Mayfield Road, Edinburgh EH9 3JR, U.K.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Fothergill-Gilmore
authors.affiliation: Research Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Université catholique de Louvain , Avenue Hippocrate 74, B-1200 Brussels, Belgium.
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh , Michael Swann Building, The King's Buildings, Mayfield Road, Edinburgh EH9 3JR, U.K.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
keywords: Trypanosoma brucei; Trypanosoma cruzi; glycolysis; high-throughput screening; inhibitors; phosphofructokinase