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. Myler; Amy Wernimont; Chris Walpole; Robin Stacy; Lynn Barrett; Ian H. Gilbert; Wesley C. Van Voorhis

doi:10.1021/acsinfecdis.6b00078

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 (Lead / Corresponding author)

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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 language	English
Pages (from-to)	34-44
Number of pages	11
Journal	ACS Infectious Diseases
Volume	3
Issue number	1
Early online date	31 Oct 2016
DOIs	https://doi.org/10.1021/acsinfecdis.6b00078
Publication status	Published - 13 Jan 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsinfecdis.6b00078Licence: CC BY

Final Published Version
ACS AuthorChoice - This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 9.44 MBLicence: CC BY

A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research

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Nakazawa Hewitt, S., Dranow, D. M., Horst, B. G., Abendroth, J. A., Forte, B., Hallyburton, I., Jansen, C., Baragana, B., Choi, R., Rivas, K., Hulverson, M. A., Dumais, M., Edwards, T. E., Lorimer, D. D., Fairlamb, A., Gray, D., Read, K., Lehane, A. M., Kirk, K., ... Van Voorhis, W. C. (2017). Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase. ACS Infectious Diseases, 3(1), 34-44. https://doi.org/10.1021/acsinfecdis.6b00078

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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 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.",

keywords = "Plasmodium falciparum, drug screening, prolyl-tRNA-synthetase, high-throughput screening, halogufinone, anti-malarials",

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

note = "Wellcome Trust (Grant no. 100476), Australian National Health, Medical Research Council (Grant no. 1042272 to K.K., and an Overseas Biomedical Fellowship 585519 to A.M.L.)",

year = "2017",

month = jan,

day = "13",

doi = "10.1021/acsinfecdis.6b00078",

language = "English",

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journal = "ACS Infectious Diseases",

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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

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T1 - Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

AU - Nakazawa Hewitt, Stephen

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.

N1 - Wellcome Trust (Grant no. 100476), Australian National Health, Medical Research Council (Grant no. 1042272 to K.K., and an Overseas Biomedical Fellowship 585519 to A.M.L.)

PY - 2017/1/13

Y1 - 2017/1/13

N2 - 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.

AB - 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.

KW - Plasmodium falciparum

KW - drug screening

KW - prolyl-tRNA-synthetase

KW - high-throughput screening

KW - halogufinone

KW - anti-malarials

U2 - 10.1021/acsinfecdis.6b00078

DO - 10.1021/acsinfecdis.6b00078

M3 - Article

C2 - 27798837

SN - 2373-8227

VL - 3

SP - 34

EP - 44

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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A Translational Engine for Biomedical Discoveries (Strategic Grant)

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