期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep40406
关键词
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资金
- the Netherlands Organization for Scientific Research (NWO), The Netherlands
- SysMo2
- Wellcome Trust
- Rosalind Franklin Fellowship from University of Groningen
- NWO Centers for Systems Biology Research grant
- EMBO short-term fellowship
- BBSRC
- FP7
- NWO
- H2020 programs [KBBE.2012.3.4-02, 311815, NFRADEV-4-2014-2015, 654248, 642691, BB/J020060/1]
- BBSRC [BB/I004696/1, BB/F003536/1, BB/I017186/1, BB/F003544/1, BB/D019079/1, BB/J020060/1, BB/F003528/1, BB/F003552/1, BB/I00470X/1, BB/I004688/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F003544/1, BB/I00470X/1, BB/F003536/1, BB/D019079/1, 1088712, BB/C008219/1, BB/F003552/1, BB/J020060/1, BB/I004688/1, BB/I017186/1, BB/I004696/1, BB/F003528/1] Funding Source: researchfish
The development of drugs that can inactivate disease-causing cells (e.g. cancer cells or parasites) without causing collateral damage to healthy or to host cells is complicated by the fact that many proteins are very similar between organisms. Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of target cell and host, a drug can limit the flux of the same essential process in one organism more than in another. We identified precise criteria for this 'network-based' drug selectivity, which can serve as an alternative or additive to structural differences. We combined computational and experimental approaches to compare energy metabolism in the causative agent of sleeping sickness, Trypanosoma brucei, with that of human erythrocytes, and identified glucose transport and glyceraldehyde-3-phosphate dehydrogenase as the most selective antiparasitic targets. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. Glucose-transport inhibitors killed trypanosomes without killing erythrocytes, neurons or liver cells.
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