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BioAssay: AID 624282

Summary of the probe development efforts to identify inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)

Name: Summary of the probe development efforts to identify inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS). ..more
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AID: 624282
Data Source: The Scripps Research Institute Molecular Screening Center (METRS_INH_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2012-06-09
Modify Date: 2013-01-24
Target
Related Experiments
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AIDNameTypeComment
624268Luminescence-based biochemical primary high throughput screening assay to identify inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Screeningdepositor-specified cross reference: Primary screen (MetRS inhibitors in singlicate)
624412Luminescence-based biochemical high throughput confirmation assay for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Screeningdepositor-specified cross reference: Confirmation assay (MetRS inhibitors in triplicate)
624413Counterscreen for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS): Luminescence-based cell-based high throughput assay to identify compounds that are cytotoxic to Jurkat human T lymphocyte cellsScreeningdepositor-specified cross reference: Counterscreen (Cytotoxicity to Jurkat human T lymphocyte cells in triplicate)
651607Fluorescent Polarization-based biochemical high throughput orthogonal assay for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Screeningdepositor-specified cross reference: Counterscreen orthogonal assay (MetRS inhibitors in triplicate)
651971Luminescence-based biochemical high throughput dose response assay for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Confirmatorydepositor-specified cross reference: Dose response (MetRS inhibitors in triplicate)
651972Counterscreen for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS): Luminescence-based cell-based high throughput dose response assay to identify compounds that are cytotoxic to Jurkat human T lymphocyte cellsConfirmatorydepositor-specified cross reference: Dose response (Cytotoxicity in triplicate)
651989Counterscreen Fluorescent Polarization-based biochemical high throughput orthogonal dose response assay for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Confirmatorydepositor-specified cross reference: Dose response counterscreen (MetRS inhibitors in triplicate)
686967Late stage luminescence-based biochemical dose response assay to identify inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Confirmatorydepositor-specified cross reference
686968Late stage counterscreen for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS): Luminescence-based cell-based high throughput dose response assay to identify compounds that are cytotoxic to Jurkat human T lymphocyte cellsConfirmatorydepositor-specified cross reference
686969Late stage counterscreen for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS): Fluorescent Polarization-based biochemical dose response orthogonal assay for inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS)Confirmatorydepositor-specified cross reference
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Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: University of Washington
Assay Provider: Wilhelmus Hol, University of Washington
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R01 AI084004-01A1
Grant Proposal PI: Wilhelmus Hol, University of Washington
External Assay ID: METRS_INH_SUMMARY

Name: Summary of the probe development efforts to identify inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS).

Description:

Human African Trypanosomiasis (HAT; also called sleeping sickness) is a neglected tropical disease that is caused by the protozoan Trypanosoma brucei, which employs the tsetse fly as its insect vector. Related tropical diseases include Chagas disease (caused by Trypanosoma cruzi) and leishmaniasis (caused by Leishmania species). Each of these diseases has a major impact on human health around the world and they lack adequate chemotherapeutic treatment options (1), as current therapies suffer from poor efficacy, oral bioavailability (2), toxicity, and difficult treatment regimens (3). As a result there is a great need to develop novel, more selective, and effective treatments (4). The aminoacyl-tRNA synthetases (aaRS) play essential roles in protein synthesis and cell survival and thus are attractive targets for the design of novel chemotherapeutic agents for these diseases (3). aaRS enzymes are essential to translating nucleotide-encoded gene sequences into proteins. Thus, inhibitors that interfere with these enzymes will inhibit formation of properly charged tRNA, leading to accumulation of uncharged tRNA on the ribosome, and disruption of normal protein chain elongation during translation, which are detrimental to cell viability. In particular, genomic studies have revealed sequence differences between the T. brucei trypanosome and mammalian methionyl-tRNA synthetases (MetRSs: which are members of the aaRS family), suggesting that selective inhibition of this enzyme and protozoan death can be achieved using drug-like molecules (2). Using RNA interference, T. brucei MetRS has been shown to be essential for parasite survival (3). In addition, since the MetRS enzymes from Trypanosomatid organisms are highly homologous (particularly in the methionine-ATP binding pocket) it is possible that compounds active against T. brucei MetRS will exhibit activity against the MetRS enzymes from T. cruzi and Leishmania.

Summary of Probe Development Effort:

This probe development effort is focused on the identification of inhibitors of Trypanosoma brucei methionyl tRNA synthetase (MetRS). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.

References:

1. Gonzalez, M. and H. Cerecetto, Novel compounds to combat trypanosomatid infections: a medicinal chemical perspective. Expert Opin Ther Pat, 2011. 21(5): p. 699-715
2. Finn, J., M. Stidham, M. Hilgers, and C.K. G, Identification of novel inhibitors of methionyl-tRNA synthetase (MetRS) by virtual screening. Bioorg Med Chem Lett, 2008. 18(14): p. 3932-7.
3. Shibata, S., J.R. Gillespie, A.M. Kelley, A.J. Napuli, Z. Zhang, K.V. Kovzun, R.M. Pefley, J. Lam, F.H. Zucker, W.C. Van Voorhis, E.A. Merritt, W.G. Hol, C.L. Verlinde, E. Fan, and F.S. Buckner, Selective inhibitors of methionyl-tRNA synthetase have potent activity against Trypanosoma brucei Infection in Mice. Antimicrob Agents Chemother, 2011. 55(5): p. 1982-9.
4. Ding, D., Q. Meng, G. Gao, Y. Zhao, Q. Wang, B. Nare, R. Jacobs, F. Rock, M.R. Alley, J.J. Plattner, G. Chen, D. Li, and H. Zhou, Design, synthesis, and structure-activity relationship of Trypanosoma brucei leucyl-tRNA synthetase inhibitors as antitrypanosomal agents. J Med Chem, 2011. 54(5): p. 1276-87.

Keywords:

Summary, Summary AID, enzyme, T. brucei, parasite, MetRS, methionyl tRNA synthetase, ligase, Aminoacyl-tRNA synthetase, aaRS, tRNA, methionine, methionyl, kinetic, biochemical, enzymatic, luciferase, luc, lumi, ATP depletion, luciferin, ATP, methionine, Luminescence, Lumi, Kinase Glo, RLU, inhibit, inhibitor, inhibition, Trypanosoma brucei., protozoa, HTS, high throughput screen, 1536, Scripps, Scripps Florida, MLSMR, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Additional Information
Grant Number: 1 R01 AI084004-01A1

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