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

[Image: see text] 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 selec...

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Autores principales: Hewitt, Stephen Nakazawa, Dranow, David M., Horst, Benjamin G., Abendroth, Jan A., Forte, Barbara, Hallyburton, Irene, Jansen, Chimed, Baragaña, Beatriz, Choi, Ryan, Rivas, Kasey L., Hulverson, Matthew A., Dumais, Mitchell, Edwards, Thomas E., Lorimer, Donald D., Fairlamb, Alan H., Gray, David W., Read, Kevin D., Lehane, Adele M., Kirk, Kiaran, Myler, Peter J., Wernimont, Amy, Walpole, Chris, Stacy, Robin, Barrett, Lynn K., Gilbert, Ian H., Van Voorhis, Wesley C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2016
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241706/
https://www.ncbi.nlm.nih.gov/pubmed/27798837
http://dx.doi.org/10.1021/acsinfecdis.6b00078
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author Hewitt, Stephen Nakazawa
Dranow, David M.
Horst, Benjamin G.
Abendroth, Jan A.
Forte, Barbara
Hallyburton, Irene
Jansen, Chimed
Baragaña, Beatriz
Choi, Ryan
Rivas, Kasey L.
Hulverson, Matthew A.
Dumais, Mitchell
Edwards, Thomas E.
Lorimer, Donald D.
Fairlamb, Alan H.
Gray, David W.
Read, Kevin D.
Lehane, Adele M.
Kirk, Kiaran
Myler, Peter J.
Wernimont, Amy
Walpole, Chris
Stacy, Robin
Barrett, Lynn K.
Gilbert, Ian H.
Van Voorhis, Wesley C.
author_facet Hewitt, Stephen Nakazawa
Dranow, David M.
Horst, Benjamin G.
Abendroth, Jan A.
Forte, Barbara
Hallyburton, Irene
Jansen, Chimed
Baragaña, Beatriz
Choi, Ryan
Rivas, Kasey L.
Hulverson, Matthew A.
Dumais, Mitchell
Edwards, Thomas E.
Lorimer, Donald D.
Fairlamb, Alan H.
Gray, David W.
Read, Kevin D.
Lehane, Adele M.
Kirk, Kiaran
Myler, Peter J.
Wernimont, Amy
Walpole, Chris
Stacy, Robin
Barrett, Lynn K.
Gilbert, Ian H.
Van Voorhis, Wesley C.
author_sort Hewitt, Stephen Nakazawa
collection PubMed
description [Image: see text] 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.
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spelling pubmed-52417062017-01-19 Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase Hewitt, Stephen Nakazawa Dranow, David M. Horst, Benjamin G. Abendroth, Jan A. Forte, Barbara Hallyburton, Irene Jansen, Chimed Baragaña, Beatriz Choi, Ryan Rivas, Kasey L. Hulverson, Matthew A. Dumais, Mitchell Edwards, Thomas E. Lorimer, Donald D. Fairlamb, Alan H. Gray, David W. Read, Kevin D. Lehane, Adele M. Kirk, Kiaran Myler, Peter J. Wernimont, Amy Walpole, Chris Stacy, Robin Barrett, Lynn K. Gilbert, Ian H. Van Voorhis, Wesley C. ACS Infect Dis [Image: see text] 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. American Chemical Society 2016-10-31 2017-01-13 /pmc/articles/PMC5241706/ /pubmed/27798837 http://dx.doi.org/10.1021/acsinfecdis.6b00078 Text en Copyright © 2016 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Hewitt, Stephen Nakazawa
Dranow, David M.
Horst, Benjamin G.
Abendroth, Jan A.
Forte, Barbara
Hallyburton, Irene
Jansen, Chimed
Baragaña, Beatriz
Choi, Ryan
Rivas, Kasey L.
Hulverson, Matthew A.
Dumais, Mitchell
Edwards, Thomas E.
Lorimer, Donald D.
Fairlamb, Alan H.
Gray, David W.
Read, Kevin D.
Lehane, Adele M.
Kirk, Kiaran
Myler, Peter J.
Wernimont, Amy
Walpole, Chris
Stacy, Robin
Barrett, Lynn K.
Gilbert, Ian H.
Van Voorhis, Wesley C.
Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase
title Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase
title_full Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase
title_fullStr Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase
title_full_unstemmed Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase
title_short Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase
title_sort biochemical and structural characterization of selective allosteric inhibitors of the plasmodium falciparum drug target, prolyl-trna-synthetase
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241706/
https://www.ncbi.nlm.nih.gov/pubmed/27798837
http://dx.doi.org/10.1021/acsinfecdis.6b00078
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