Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.

Autor: Hewitt SN; 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., Dranow DM; 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., Horst BG; 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., Abendroth JA; 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., Forte B; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Hallyburton I; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Jansen C; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Baragaña B; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Choi R; 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., Rivas KL; Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States., Hulverson MA; Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States., Dumais M; Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States., Edwards TE; 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., Lorimer DD; Beryllium Discovery Corporation , 7869 N.E. Day Road West, Bainbridge Island, Washington 98110, United States., Fairlamb AH; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Gray DW; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Read KD; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Lehane AM; Research School of Biology, The Australian National University , Acton, Australian Capital Territory 2601, Australia., Kirk K; Research School of Biology, The Australian National University , Acton, Australian Capital Territory 2601, Australia., Myler PJ; 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., Wernimont A; Structure-guided Drug Discovery Coalition (SDDC), Structural Genomic Consortium , 101 College Street, MaRS South Tower, Suite 700, Toronto, Ontario M5G 1L7, Canada., Walpole C; Structure-guided Drug Discovery Coalition (SDDC), Structural Genomic Consortium , 101 College Street, MaRS South Tower, Suite 700, Toronto, Ontario M5G 1L7, Canada., Stacy R; 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., Barrett LK; 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., Gilbert IH; Drug Discovery Unit (DDU), Division of Biological Chemistry and Drug Discovery, University of Dundee , Dundee DD1 5EH, United Kingdom., Van Voorhis WC; 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.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2017 Jan 13; Vol. 3 (1), pp. 34-44. Date of Electronic Publication: 2016 Nov 16.
DOI: 10.1021/acsinfecdis.6b00078
Abstrakt: 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.
Databáze: MEDLINE
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