Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani

Leah Torrie; Stephen Brand; David Robinson; Eun Jung Ko; Laste Stojanovski; Frederick R. C. Simeons; Susan Wyllie; John Thomas; Lucy Ellis; Maria Osuna-Cabello; Rafiu Epemolu; Andrea Nuehs; Jennifer Riley; Lorna MacLean; Sujatha Manthri; Kevin Read; Ian Gilbert; Alan Fairlamb; Manu De Rycker

doi:10.1021/acsinfecdis.7b00047

Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani

Leah Torrie, Stephen Brand, David Robinson, Eun Jung Ko, Laste Stojanovski, Frederick R. C. Simeons, Susan Wyllie, John Thomas, Lucy Ellis, Maria Osuna-Cabello, Rafiu Epemolu, Andrea Nuehs, Jennifer Riley, Lorna MacLean, Sujatha Manthri, Kevin Read, Ian Gilbert (Lead / Corresponding author), Alan Fairlamb, Manu De Rycker (Lead / Corresponding author)

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

20 Citations (Scopus)

237 Downloads (Pure)

Abstract

Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust highthroughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable anti-leishmanial compound, MetRS remains an attractive anti-leishmanial drug target.

Original language	English
Pages (from-to)	718-727
Number of pages	10
Journal	ACS Infectious Diseases
Volume	3
Issue number	10
Early online date	2 Oct 2017
DOIs	https://doi.org/10.1021/acsinfecdis.7b00047
Publication status	Published - Oct 2017

Keywords

Drug Discovery
Kinetoplastids
Translation
tRNA synthetase
Parasite

Access to Document

10.1021/acsinfecdis.7b00047Licence: CC BY

Final Published Version
© 2017 American Chemical Society. 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, 4.61 MBLicence: CC BY

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)
Fairlamb, A. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Horn, D. (Investigator) & Wyatt, P. (Investigator)
1/01/15 → 31/12/20
Project: Research
A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research
Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)
Brenk, R. (Investigator), Fairlamb, A. (Investigator), Ferguson, M. (Investigator), Field, M. (Investigator), Gilbert, I. (Investigator), Gray, D. (Investigator), Hopkins, A. (Investigator), Horn, D. (Investigator), Read, K. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/02/11 → 1/07/17
Project: Research

Gilbert, Ian
- Drug Discovery Unit - Professor/Head of the Drug Discovery Unit & Roscoe Chair in Drug Discovery
Person: Academic

Cite this

Torrie, L., Brand, S., Robinson, D., Ko, E. J., Stojanovski, L., Simeons, F. R. C., Wyllie, S., Thomas, J., Ellis, L., Osuna-Cabello, M., Epemolu, R., Nuehs, A., Riley, J., MacLean, L., Manthri, S., Read, K., Gilbert, I., Fairlamb, A., & De Rycker, M. (2017). Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani. ACS Infectious Diseases, 3(10), 718-727. https://doi.org/10.1021/acsinfecdis.7b00047

@article{efe228b9806c4c778cb5c9e519f8a5d4,

title = "Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani",

abstract = "Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust highthroughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable anti-leishmanial compound, MetRS remains an attractive anti-leishmanial drug target.",

keywords = "Drug Discovery, Kinetoplastids, Translation, tRNA synthetase, Parasite ",

author = "Leah Torrie and Stephen Brand and David Robinson and Ko, {Eun Jung} and Laste Stojanovski and Simeons, {Frederick R. C.} and Susan Wyllie and John Thomas and Lucy Ellis and Maria Osuna-Cabello and Rafiu Epemolu and Andrea Nuehs and Jennifer Riley and Lorna MacLean and Sujatha Manthri and Kevin Read and Ian Gilbert and Alan Fairlamb and {De Rycker}, Manu",

note = "We would like to acknowledge the Wellcome Trust for funding (grants 092340, 105021, 100476). We would like to acknowledge GSK for provision of the TCAMS (Tres Cantos Anti-Malarial Set) for screening against the kinetoplastids and some additional bacterial MetRS inhibitors. We also acknowledge the support of the Protein Production Team in the Division of Biological Chemistry and Drug Discovery (Dundee), the Drug Discovery Unit compound management, and Drug Discovery Unit data management teams. The authors would like to thank Diamond Light Source for beamtime (proposal mx8268), and the staff of beamlines I02 and I04 for assistance with data collection",

year = "2017",

month = oct,

doi = "10.1021/acsinfecdis.7b00047",

language = "English",

volume = "3",

pages = "718--727",

journal = "ACS Infectious Diseases",

issn = "2373-8227",

publisher = "American Chemical Society",

number = "10",

}

Torrie, L, Brand, S, Robinson, D, Ko, EJ, Stojanovski, L, Simeons, FRC, Wyllie, S , Thomas, J, Ellis, L, Osuna-Cabello, M, Epemolu, R, Nuehs, A, Riley, J, MacLean, L, Manthri, S, Read, K , Gilbert, I , Fairlamb, A & De Rycker, M 2017, 'Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani', ACS Infectious Diseases, vol. 3, no. 10, pp. 718-727. https://doi.org/10.1021/acsinfecdis.7b00047

TY - JOUR

T1 - Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani

AU - Torrie, Leah

AU - Brand, Stephen

AU - Robinson, David

AU - Ko, Eun Jung

AU - Stojanovski, Laste

AU - Simeons, Frederick R. C.

AU - Wyllie, Susan

AU - Thomas, John

AU - Ellis, Lucy

AU - Osuna-Cabello, Maria

AU - Epemolu, Rafiu

AU - Nuehs, Andrea

AU - Riley, Jennifer

AU - MacLean, Lorna

AU - Manthri, Sujatha

AU - Read, Kevin

AU - Gilbert, Ian

AU - Fairlamb, Alan

AU - De Rycker, Manu

N1 - We would like to acknowledge the Wellcome Trust for funding (grants 092340, 105021, 100476). We would like to acknowledge GSK for provision of the TCAMS (Tres Cantos Anti-Malarial Set) for screening against the kinetoplastids and some additional bacterial MetRS inhibitors. We also acknowledge the support of the Protein Production Team in the Division of Biological Chemistry and Drug Discovery (Dundee), the Drug Discovery Unit compound management, and Drug Discovery Unit data management teams. The authors would like to thank Diamond Light Source for beamtime (proposal mx8268), and the staff of beamlines I02 and I04 for assistance with data collection

PY - 2017/10

Y1 - 2017/10

N2 - Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust highthroughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable anti-leishmanial compound, MetRS remains an attractive anti-leishmanial drug target.

AB - Methionyl-tRNA synthetase (MetRS) has been chemically validated as a drug target in the kinetoplastid parasite Trypanosoma brucei. In the present study we investigate the validity of this target in the related trypanosomatid Leishmania donovani. Following development of a robust highthroughput compatible biochemical assay, a compound screen identified DDD806905 as a highly potent inhibitor of LdMetRS (Ki 18 nM). Crystallography revealed this compound binds to the methionine pocket of MetRS with enzymatic studies confirming DDD806905 displays competitive inhibition with respect to methionine and mixed inhibition with respect to ATP binding. DDD806905 showed activity, albeit with different levels of potency, in various Leishmania cell-based viability assays, with on-target activity observed in both Leishmania promastigote cell assays and a Leishmania tarentolae in vitro translation assay. Unfortunately this compound failed to show efficacy in an animal model of leishmaniasis. We investigated the potential causes for the discrepancies in activity observed in different Leishmania cell assays and the lack of efficacy in the animal model and found that high protein binding as well as sequestration of this dibasic compound into acidic compartments may play a role. Despite medicinal chemistry efforts to address the dibasic nature of DDD806905 and analogues, no progress could be achieved with the current chemical series. Although DDD806905 is not a developable anti-leishmanial compound, MetRS remains an attractive anti-leishmanial drug target.

KW - Drug Discovery

KW - Kinetoplastids

KW - Translation

KW - tRNA synthetase

KW - Parasite

U2 - 10.1021/acsinfecdis.7b00047

DO - 10.1021/acsinfecdis.7b00047

M3 - Article

C2 - 28967262

SN - 2373-8227

VL - 3

SP - 718

EP - 727

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

IS - 10

ER -

Chemical Validation of Methionyl tRNA Synthetase (MetRS) as a Druggable Target in Leishmania donovani

Abstract

Keywords

Access to Document

Fingerprint

Projects

Chemical Biology: Leveraging Phenotypic Hits Against Kinetoplastids (Strategic Grant)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Profiles

Gilbert, Ian

Cite this