RESUMEN
Quinomycin A and its derivatives were identified as potent antimalarial (Plasmodium falciparum) agents in a screen of the RIKEN NPDepo chemical library. IC50 values of quinomycin A and UK-63,598 were approximately 100 times lower than that of the antimalarial drug chloroquine. This activity was mitigated by the addition of plasmid DNA, suggesting that these compounds act against parasites by intercalating into their DNA.
Asunto(s)
Antimaláricos/farmacología , ADN Protozoario/antagonistas & inhibidores , Equinomicina/farmacología , Sustancias Intercalantes/farmacología , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/química , Cloroquina/farmacología , ADN Protozoario/química , Descubrimiento de Drogas , Equinomicina/química , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Humanos , Concentración 50 Inhibidora , Sustancias Intercalantes/química , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , Plásmidos/química , Plásmidos/farmacología , Plasmodium falciparum/enzimología , Plasmodium falciparum/crecimiento & desarrollo , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
DNA topoisomerase II from Plasmodium falciparum was partially purified by FPLC using three columns: Econo-Pac Q, heparin-agarose and Mono Q. The enzyme showed ATP- and Mg2 +/- dependent activities in a decatenation assay, with optimum concentrations of 0.5 and 10 mM, respectively. Furthermore, highest activity was detected in the presence of 100 mM KCI. Enzyme decatenation activity was not inhibited by the DNA topoisomerase I inhibitor, camptothecin, but was sensitive to both prokaryotic and eukaryotic DNA topoisomerase II inhibitors.
Asunto(s)
ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/aislamiento & purificación , ADN Protozoario/química , ADN Protozoario/aislamiento & purificación , Plasmodium falciparum/genética , Animales , Antiinfecciosos/farmacología , Camptotecina/farmacología , Cromatografía en Agarosa , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , ADN Protozoario/antagonistas & inhibidores , ADN Protozoario/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Electroforesis en Gel Bidimensional , Células Eucariotas , Fluoroquinolonas , Pruebas de Sensibilidad Microbiana , Células Procariotas , Inhibidores de Topoisomerasa IIRESUMEN
The increasing demand for novel anti-parasitic drugs due to resistance formation to well-established chemotherapeutically important compounds has increased the demands for a better understanding of the mechanism(s) of action of existing drugs and of drugs in development. While different approaches have been developed to identify the targets and thus mode of action of anti-parasitic compounds, it has become clear that many drugs act not only on one, but possibly several parasite molecules or even pathways. Ideally, these targets are not present in any cells of the host. In the case of apicomplexan parasites, the unique apicoplast, provides a suitable target for compounds binding to DNA or ribosomal RNA of prokaryotic origin. In the case of intracellular pathogens, a given drug might not only affect the pathogen by directly acting on parasite-associated targets, but also indirectly, by altering the host cell physiology. This in turn could affect the parasite development and lead to parasite death. In this review, we provide an overview of strategies for target identification, and present examples of selected drug targets, ranging from proteins to nucleic acids to intermediary metabolism.