RESUMO
Mature gametocytes, the sexual stage of Plasmodium falciparum, ensure the continued transmission of malaria from the human host to the mosquito vector. Even if gametocytes are not implicated in the malaria physiopathology it is crucial to the spread of malaria. Gametocytes are to be a key target for drugs used against Plasmodium in public health. The expression levels of 4 sexual-stage specific genes, Pfs 16, Pfs 25, Pfg 27 and S 18S rRNA, during gametocytogenesis of various P. falciparum strains were analyzed by a real time PCR assay. The strains showed different capacities to produce mature gametocytes and in parallel different patterns of sexual gene expression. There was a correlation only between Pfs 16 cDNA overexpression in the first 48h of the culture and the production of mature gametocytes. Pfs 16 is an early marker of the development of mature gametocytes in cultures and is therefore a potential target for new antimalarial drugs.
Assuntos
Antígenos de Protozoários/fisiologia , Gametogênese/fisiologia , Regulação da Expressão Gênica/fisiologia , Malária Falciparum/transmissão , Proteínas de Membrana/fisiologia , Plasmodium falciparum/fisiologia , Animais , Antígenos de Protozoários/biossíntese , Antígenos de Protozoários/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Gametogênese/efeitos dos fármacos , Gametogênese/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Plasmodium falciparum/efeitos dos fármacos , RNA de Protozoário/sangue , RNA de Protozoário/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Malaria is the third most significant cause of infectious disease in the world. The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to classical drugs. Trioxaquines are synthetic hybrid molecules containing a trioxane motif (which is responsible for the antimalarial activity of artemisinin) linked to an aminoquinoline entity (which is responsible for the antiplasmodial properties of chloroquine). These trioxaquines are highly potent against young erythrocytic stages of Plasmodium falciparum and exhibit efficient activity in vitro against chloroquine-sensitive and -resistant strains of P. falciparum (50% inhibitory concentration, 4 to 32 nM) and are also active in vivo against P. vinckei petteri and P. yoelii nigeriensis in suppressive and curative murine tests. The trioxaquine DU1302 is one of these promising antimalarial agents. The present study confirms the absence of toxicity of this drug on cell lines and in a mice model. Moreover, DU1302 exhibits potent activity against gametocytes, the form transmitted by mosquitoes, as killing of the gametocytes is essential to limit the spread of malaria. The ease of chemical synthesis of this trioxaquine prototype should be considered an additional advantage and would make these drugs affordable without perturbations of the drug supply.
