title: Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.
abstract: Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with PfProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.|Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.
authors: Stephen Nakazawa
authors: SN
authors: Hewitt
authors: Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.|Beryllium Discovery Corporation , 7869 N.E. Day Road West, Bainbridge Island, Washington 98110, United States.
authors: David M
authors: DM
authors: Dranow
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.|Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.
authors: Benjamin G
authors: BG
authors: Horst
authors: Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.|Beryllium Discovery Corporation , 7869 N.E. Day Road West, Bainbridge Island, Washington 98110, United States.
authors: Jan A
authors: JA
authors: Abendroth
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Barbara
authors: B
authors: Forte
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Irene
authors: I
authors: Hallyburton
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Chimed
authors: C
authors: Jansen
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Beatriz
authors: B
authors: Baragaña
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.|Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.
authors: Ryan
authors: R
authors: Choi
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors: Kasey L
authors: KL
authors: Rivas
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors: Matthew A
authors: MA
authors: Hulverson
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.
authors: Mitchell
authors: M
authors: Dumais
authors: Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.|Beryllium Discovery Corporation , 7869 N.E. Day Road West, Bainbridge Island, Washington 98110, United States.
authors: Thomas E
authors: TE
authors: Edwards
authors: Beryllium Discovery Corporation , 7869 N.E. Day Road West, Bainbridge Island, Washington 98110, United States.
authors: Donald D
authors: DD
authors: Lorimer
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Alan H
authors: AH
authors: Fairlamb
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: David W
authors: DW
authors: Gray
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Kevin D
authors: KD
authors: Read
authors: Research School of Biology, The Australian National University , Acton, Australian Capital Territory 2601, Australia.
authors: Adele M
authors: AM
authors: Lehane
authors: Research School of Biology, The Australian National University , Acton, Australian Capital Territory 2601, Australia.
authors: Kiaran
authors: K
authors: Kirk
authors: Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.|Center for Infectious Disease Research , 307 Westlake Avenue North, Suite 500, Seattle, Washington 98109, United States.|Departments of Global Health and Biomedical Informatics and Medical Education, University of Washington , Seattle, Washington 98195, United States.
authors: Peter J
authors: PJ
authors: Myler
authors: Structure-guided Drug Discovery Coalition (SDDC), Structural Genomic Consortium , 101 College Street, MaRS South Tower, Suite 700, Toronto, Ontario M5G 1L7, Canada.
authors: Amy
authors: A
authors: Wernimont
authors: Structure-guided Drug Discovery Coalition (SDDC), Structural Genomic Consortium , 101 College Street, MaRS South Tower, Suite 700, Toronto, Ontario M5G 1L7, Canada.
authors: Chris
authors: C
authors: Walpole
authors: Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.|Center for Infectious Disease Research , 307 Westlake Avenue North, Suite 500, Seattle, Washington 98109, United States.
authors: Robin
authors: R
authors: Stacy
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.|Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.
authors: Lynn K
authors: LK
authors: Barrett
authors: Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom.
authors: Ian H
authors: IH
authors: Gilbert
authors: Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.|Seattle Structural Genomics Center for Infectious Disease (SSGCID) , Seattle, Washington 98109, United States.
authors: Wesley C
authors: WC
authors: Van Voorhis
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors*; D000962:Antimalarials / Q000494:pharmacology*; D001665:Binding Sites; D003001:Cloning, Molecular; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011487:Protein Conformation; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D000604:Amino Acyl-tRNA Synthetases
keywords: Plasmodium falciparum; antimalarials; drug screening; halofuginone; high-throughput screening; prolyl-tRNA-synthetase