RESUMO
Over the past thirty years, epigenetic regulation of gene expression has gained increasing interest as it was shown to be implicated in illnesses ranging from cancers to parasitic diseases. In the malaria parasite, epigenetics was shown to be involved in several key steps of the complex life cycle of Plasmodium, among which asexual development and sexual commitment, but also in major biological processes like immune evasion, response to environmental changes or DNA repair. Because epigenetics plays such paramount roles in the Plasmodium parasite, enzymes involved in these regulating pathways represent a reservoir of potential therapeutic targets. This review focuses on epigenetic regulatory processes and their effectors in the malaria parasite, as well as the inhibitors of epigenetic pathways and their potential as new anti-malarial drugs. Such types of drugs could be formidable tools that may contribute to malaria eradication in a context of widespread resistance to conventional anti-malarials.
Assuntos
Antimaláricos , Malária Falciparum , Malária , Parasitos , Plasmodium , Animais , Humanos , Plasmodium falciparum , Malária Falciparum/parasitologia , Epigênese Genética , Malária/parasitologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêuticoRESUMO
This study measured the antiplasmodial activity of nine zinc-dipicolylamine (ZnDPA) complexes against three strains of Plasmodium falciparum, the causative parasite of malaria. Growth inhibition assays showed significant activity against all tested strains, with 50% inhibitory concentrations between 5 and 600nM and almost no toxic effect against host cells including healthy red blood cells. Fluorescence microscopy studies with a green-fluorescent ZnDPA probe showed selective targeting of infected red blood cells. The results suggest that ZnDPA coordination complexes are promising antiplasmodial agents with potential for targeted malaria treatment.
Assuntos
Antimaláricos/química , Complexos de Coordenação/química , Compostos Organometálicos/química , Picolinas/química , Animais , Antimaláricos/síntese química , Antimaláricos/uso terapêutico , Antimaláricos/toxicidade , Células CHO , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/uso terapêutico , Complexos de Coordenação/toxicidade , Cricetinae , Cricetulus , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Hemólise/efeitos dos fármacos , Humanos , Malária/tratamento farmacológico , Microscopia de Fluorescência , Plasmodium falciparum/efeitos dos fármacosRESUMO
A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50=210nM) close to the value obtained with chloroquine (IC50=514nM) and a weak cytotoxicity.