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 Baragaña; Ryan Choi; Kasey L. Rivas; Matthew A. Hulverson; Mitchell Dumais; Thomas E. Edwards; Donald D. Lorimer; Alan H. Fairlamb; David W. Gray; Kevin D. Read; Adele M. Lehane; Kiaran Kirk; Peter J. Myler; Amy Wernimont; Chris Walpole; Robin Stacy; Lynn K. 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 Baragaña, Ryan Choi, Kasey L. Rivas, Matthew A. Hulverson, Mitchell Dumais, Thomas E. Edwards, Donald D. Lorimer, Alan H. Fairlamb, David W. Gray, Kevin D. Read, Adele M. Lehane, Kiaran Kirk, Peter J. MylerAmy Wernimont, Chris Walpole, Robin Stacy, Lynn K. Barrett, Ian H. Gilbert, Wesley C. Van Voorhis^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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 Pf ProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of Pf ProRS. We identified two new inhibitors of Pf ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for Pf ProRS 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 Pf ProRS, 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
DOIs	https://doi.org/10.1021/acsinfecdis.6b00078
Publication status	Published - 13 Jan 2017

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Hewitt, S. N., Dranow, D. M., Horst, B. G., Abendroth, J. A., Forte, B., Hallyburton, I., Jansen, C., Baragaña, B., Choi, R., Rivas, K. L., Hulverson, M. A., Dumais, M., Edwards, T. E., Lorimer, D. D., Fairlamb, A. H., Gray, D. W., Read, K. D., 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

@article{2968d7c14c5c4eda93f9fa38d7aab695,

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 Pf ProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of Pf ProRS. We identified two new inhibitors of Pf ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for Pf ProRS 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 Pf ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.",

keywords = "Antimalarials, Drug screening, Halofuginone, High-throughput screening, Plasmodium falciparum, Prolyl-tRNA-synthetase",

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

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2017",

month = jan,

day = "13",

doi = "10.1021/acsinfecdis.6b00078",

language = "English",

volume = "3",

pages = "34--44",

journal = "ACS Infectious Diseases",

issn = "2373-8227",

publisher = "American Chemical Society",

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Hewitt, SN, Dranow, DM, Horst, BG, Abendroth, JA, Forte, B, Hallyburton, I, Jansen, C, Baragaña, B, Choi, R, Rivas, KL, Hulverson, MA, Dumais, M, Edwards, TE, Lorimer, DD, Fairlamb, AH, Gray, DW, Read, KD, Lehane, AM , Kirk, K, Myler, PJ, Wernimont, A, Walpole, C, Stacy, R, Barrett, LK, 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

TY - JOUR

T1 - Biochemical and structural characterization of selective allosteric inhibitors of the Plasmodium falciparum drug target, prolyl-tRNA-synthetase

AU - Hewitt, Stephen Nakazawa

AU - Dranow, David M.

AU - Horst, Benjamin G.

AU - Abendroth, Jan A.

AU - Forte, Barbara

AU - Hallyburton, Irene

AU - Jansen, Chimed

AU - Baragaña, Beatriz

AU - Choi, Ryan

AU - Rivas, Kasey L.

AU - Hulverson, Matthew A.

AU - Dumais, Mitchell

AU - Edwards, Thomas E.

AU - Lorimer, Donald D.

AU - Fairlamb, Alan H.

AU - Gray, David W.

AU - Read, Kevin D.

AU - Lehane, Adele M.

AU - Kirk, Kiaran

AU - Myler, Peter J.

AU - Wernimont, Amy

AU - Walpole, Chris

AU - Stacy, Robin

AU - Barrett, Lynn K.

AU - Gilbert, Ian H.

AU - Van Voorhis, Wesley C.

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 Pf ProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of Pf ProRS. We identified two new inhibitors of Pf ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for Pf ProRS 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 Pf ProRS, 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 Pf ProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of Pf ProRS. We identified two new inhibitors of Pf ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for Pf ProRS 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 Pf ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.

KW - Antimalarials

KW - Drug screening

KW - Halofuginone

KW - High-throughput screening

KW - Plasmodium falciparum

KW - Prolyl-tRNA-synthetase

UR - http://www.scopus.com/inward/record.url?scp=85035745858&partnerID=8YFLogxK

U2 - 10.1021/acsinfecdis.6b00078

DO - 10.1021/acsinfecdis.6b00078

M3 - Article

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

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