Scientific reports, 2016-11, Vol.6 (1), p.37502, Article 37502
2016
Details
- Autor(en) / Beteiligte
- Titel
- Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum
- Ist Teil von
- Scientific reports, 2016-11, Vol.6 (1), p.37502, Article 37502
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Plasmodium parasites are responsible for the devastating disease malaria that affects hundreds of millions of people each year. Blood stage parasites establish new permeability pathways (NPPs) in infected red blood cell membranes to facilitate the uptake of nutrients and removal of parasite waste products. Pharmacological inhibition of the NPPs is expected to lead to nutrient starvation and accumulation of toxic metabolites resulting in parasite death. Here, we have screened a curated library of antimalarial compounds, the MMV Malaria Box, identifying two compounds that inhibit NPP function. Unexpectedly, metabolic profiling suggested that both compounds also inhibit dihydroorotate dehydrogense (DHODH), which is required for pyrimidine synthesis and is a validated drug target in its own right. Expression of yeast DHODH, which bypasses the need for the parasite DHODH, increased parasite resistance to these compounds. These studies identify two potential candidates for therapeutic development that simultaneously target two essential pathways in Plasmodium, NPP and DHODH.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/srep37502Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5118696
- Format
- –
- Schlagworte
- Animals, Antimalarials - analysis, Antimalarials - chemistry, Antimalarials - pharmacology, Blood, Cell Membrane Permeability - drug effects, Cell membranes, Cell Proliferation - drug effects, Dihydroorotate Dehydrogenase, Drug Evaluation, Preclinical, Electron Transport Complex III - metabolism, Enzyme Inhibitors - analysis, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Erythrocytes, Erythrocytes - drug effects, Erythrocytes - parasitology, Genes, Reporter, High-Throughput Screening Assays, Inhibitory Concentration 50, Life Cycle Stages - drug effects, Luciferases - metabolism, Malaria, Membrane permeability, Metabolites, Metabolomics, Nutrients, Oxidoreductases Acting on CH-CH Group Donors - metabolism, Parasite resistance, Parasites, Parasites - drug effects, Parasites - enzymology, Parasites - growth & development, Permeability, Plasmodium falciparum, Plasmodium falciparum - drug effects, Plasmodium falciparum - enzymology, Plasmodium falciparum - growth & development, Reproducibility of Results, Saccharomyces cerevisiae - metabolism, Sorbitol - pharmacology