Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase
Abstract
New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. In this study, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood–brain barrier penetration. The medicinal chemistry program elucidated structure–activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.
- Authors:
-
[1];
[1]
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
- Scynexis, Inc., Durham, NC (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); Welch Foundation
- OSTI Identifier:
- 1570753
- Grant/Contract Number:
- AC02-06CH11357; 2R37AI034432; R01AI090599; I-1257; I-1422
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 61; Journal Issue: 3; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; assays; inhibitors; inhibition; peptides and proteins; layers; human African trypanosomiasis; Trypanosoma brucei; AdoMetDC; pyrimidineamine; co-crystallization
Citation Formats
Volkov, Oleg A., Brockway, Anthony J., Wring, Stephen A., Peel, Michael, Chen, Zhe, Phillips, Margaret A., and De Brabander, Jef K. Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase. United States: N. p., 2018.
Web. doi:10.1021/acs.jmedchem.7b01654.
Volkov, Oleg A., Brockway, Anthony J., Wring, Stephen A., Peel, Michael, Chen, Zhe, Phillips, Margaret A., & De Brabander, Jef K. Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase. United States. https://doi.org/10.1021/acs.jmedchem.7b01654
Volkov, Oleg A., Brockway, Anthony J., Wring, Stephen A., Peel, Michael, Chen, Zhe, Phillips, Margaret A., and De Brabander, Jef K. Fri .
"Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase". United States. https://doi.org/10.1021/acs.jmedchem.7b01654. https://www.osti.gov/servlets/purl/1570753.
@article{osti_1570753,
title = {Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase},
author = {Volkov, Oleg A. and Brockway, Anthony J. and Wring, Stephen A. and Peel, Michael and Chen, Zhe and Phillips, Margaret A. and De Brabander, Jef K.},
abstractNote = {New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. In this study, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood–brain barrier penetration. The medicinal chemistry program elucidated structure–activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.},
doi = {10.1021/acs.jmedchem.7b01654},
journal = {Journal of Medicinal Chemistry},
number = 3,
volume = 61,
place = {United States},
year = {Fri Jan 05 00:00:00 EST 2018},
month = {Fri Jan 05 00:00:00 EST 2018}
}
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Works referencing / citing this record:
A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei
journal, October 2018
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Polyamines in protozoan pathogens
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A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei
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