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

Stephen Nakazawa Hewitt, David M. Dranow, Benjamin G. Horst, Jan A. Abendroth, Barbara Forte, Irene Hallyburton, Chimed Jansen, Beatriz Baragana, Ryan Choi, Kasey Rivas, Matthew A. Hulverson, Mitchell Dumais, Thomas E. Edwards, Donald D. Lorimer, Alan Fairlamb, David Gray, Kevin Read, Adele M. Lehane, Kiaran Kirk, Peter J. MylerAmy Wernimont, Chris Walpole, Robin Stacy, Lynn Barrett, Ian H. Gilbert, Wesley C. Van Voorhis

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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 vs. H. 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 >100X specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogs. Initial medicinal chemistry was performed on one of the two compounds, guided by the co-crystallography 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.
Original languageEnglish
Pages (from-to)34-44
Number of pages11
JournalACS Infectious Diseases
Volume3
Issue number1
Early online date31 Oct 2016
DOIs
Publication statusPublished - 13 Jan 2017

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Pharmaceutical Chemistry
Plasmodium falciparum
Malaria
Crystallography
X Ray Crystallography
Pharmaceutical Preparations
Catalytic Domain
Enzymes
prolyl T RNA synthetase
halofuginone

Keywords

  • Plasmodium falciparum
  • drug screening
  • prolyl-tRNA-synthetase
  • high-throughput screening
  • halogufinone
  • anti-malarials

Cite this

Nakazawa Hewitt, Stephen ; Dranow, David M. ; Horst, Benjamin G. ; Abendroth, Jan A. ; Forte, Barbara ; Hallyburton, Irene ; Jansen, Chimed ; Baragana, Beatriz ; Choi, Ryan ; Rivas, Kasey ; Hulverson, Matthew A. ; Dumais, Mitchell ; Edwards, Thomas E. ; Lorimer, Donald D. ; Fairlamb, Alan ; Gray, David ; Read, Kevin ; Lehane, Adele M. ; Kirk, Kiaran ; Myler, Peter J. ; Wernimont, Amy ; Walpole, Chris ; Stacy, Robin ; Barrett, Lynn ; Gilbert, Ian H. ; Van Voorhis, Wesley C. / Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase. In: ACS Infectious Diseases. 2017 ; Vol. 3, No. 1. pp. 34-44.
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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 vs. H. 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 >100X specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogs. Initial medicinal chemistry was performed on one of the two compounds, guided by the co-crystallography 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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Nakazawa Hewitt, S, Dranow, DM, Horst, BG, Abendroth, JA, Forte, B, Hallyburton, I, Jansen, C, Baragana, B, Choi, R, Rivas, K, Hulverson, MA, Dumais, M, Edwards, TE, Lorimer, DD, Fairlamb, A, Gray, D, Read, K, Lehane, AM, Kirk, K, Myler, PJ, Wernimont, A, Walpole, C, Stacy, R, Barrett, L, Gilbert, IH & Van Voorhis, WC 2017, 'Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase', ACS Infectious Diseases, vol. 3, no. 1, pp. 34-44. https://doi.org/10.1021/acsinfecdis.6b00078

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase. / Nakazawa Hewitt, Stephen; Dranow, David M.; Horst, Benjamin G.; Abendroth, Jan A.; Forte, Barbara; Hallyburton, Irene; Jansen, Chimed; Baragana, Beatriz; Choi, Ryan; Rivas, Kasey; Hulverson, Matthew A.; Dumais, Mitchell; Edwards, Thomas E.; Lorimer, Donald D.; Fairlamb, Alan; Gray, David; Read, Kevin; Lehane, Adele M.; Kirk, Kiaran; Myler, Peter J.; Wernimont, Amy; Walpole, Chris; Stacy, Robin; Barrett, Lynn; Gilbert, Ian H.; Van Voorhis, Wesley C. (Lead / Corresponding author).

In: ACS Infectious Diseases, Vol. 3, No. 1, 13.01.2017, p. 34-44.

Research output: Contribution to journalArticle

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AU - Dranow, David M.

AU - Horst, Benjamin G.

AU - Abendroth, Jan A.

AU - Forte, Barbara

AU - Hallyburton, Irene

AU - Jansen, Chimed

AU - Baragana, Beatriz

AU - Choi, Ryan

AU - Rivas, Kasey

AU - Hulverson, Matthew A.

AU - Dumais, Mitchell

AU - Edwards, Thomas E.

AU - Lorimer, Donald D.

AU - Fairlamb, Alan

AU - Gray, David

AU - Read, Kevin

AU - Lehane, Adele M.

AU - Kirk, Kiaran

AU - Myler, Peter J.

AU - Wernimont, Amy

AU - Walpole, Chris

AU - Stacy, Robin

AU - Barrett, Lynn

AU - Gilbert, Ian H.

AU - Van Voorhis, Wesley C.

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KW - drug screening

KW - prolyl-tRNA-synthetase

KW - high-throughput screening

KW - halogufinone

KW - anti-malarials

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