Use of a selective inhibitor to define the chemotherapeutic potential of the plasmodial hexose transporter in different stages of the parasite's life cycle
| Autor: | Robert E. Sinden, Elvira T. Derbyshire, Christophe Morin, Henry M. Staines, Michael J. Delves, Ursula Straschil, Rita Tewari, Maria M. Mota, Zhengyao Xu, Arthur M. Talman, Ksenija Slavic, Sanjeev Krishna, Miguel Prudêncio |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Erythrocytes
Monosaccharide Transport Proteins Plasmodium berghei 030231 tropical medicine Green fluorescent protein Antimalarials Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Animals Humans Parasite hosting Pharmacology (medical) Hexose Mechanisms of Action: Physiological Effects 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology Transporter Plasmodium falciparum biology.organism_classification 3. Good health Glucose Infectious Diseases Liver chemistry Biochemistry Cell culture Energy source |
| Zdroj: | Antimicrobial Agents and Chemotherapy; Vol 55 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | During blood infection, malarial parasites use d -glucose as their main energy source. The Plasmodium falciparum hexose transporter (PfHT), which mediates the uptake of d -glucose into parasites, is essential for survival of asexual blood-stage parasites. Recently, genetic studies in the rodent malaria model, Plasmodium berghei , found that the orthologous hexose transporter (PbHT) is expressed throughout the parasite's development within the mosquito vector, in addition to being essential during intraerythrocytic development. Here, using a d -glucose-derived specific inhibitor of plasmodial hexose transporters, compound 3361, we have investigated the importance of d -glucose uptake during liver and transmission stages of P. berghei . Initially, we confirmed the expression of PbHT during liver stage development, using a green fluorescent protein (GFP) tagging strategy. Compound 3361 inhibited liver-stage parasite development, with a 50% inhibitory concentration (IC 50 ) of 11 μM. This process was insensitive to the external d -glucose concentration. In addition, compound 3361 inhibited ookinete development and microgametogenesis, with IC 50 s in the region of 250 μM (the latter in a d -glucose-sensitive manner). Consistent with our findings for the effect of compound 3361 on vector parasite stages, 1 mM compound 3361 demonstrated transmission blocking activity. These data indicate that novel chemotherapeutic interventions that target PfHT may be active against liver and, to a lesser extent, transmission stages, in addition to blood stages. |
| Databáze: | OpenAIRE |
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