Identificação de novos fármacos antimaláricos através de estratégia de quimiogenômica por reposicionamento e validação experimental

• Autor(a) principal: Rodrigues, Juliana
• Data de Publicação: 2018
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/0013000004cqq
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/10952
• topic: Malária; Tratamento; Resposicionamento de fármacos; Quimiogenômica; Epirrubicina; Malaria; Treatment; Drug repositioning; Chemogenomics; Epirubicin; CIENCIAS DA SAUDE

Malaria is an infectious disease of possible chronic evolution that affects billions of people in the tropics and subtropics. P. falciparum is the most lethal malaria parasite of humans, while P. vivax is the most widely distributed. The effectiveness of the antimalarial treatment is compromised by the ability of the parasite to evolve resistance to the compounds and by the lack of new effective antimalarials, underscoring the urgent need for the discovery of new drugs. One of the strategies that has been gradually explored in the search for new therapies is the so-called "drug repurposing" approach. In this context, the goal of the present study was to use a drug repurposing-chemogenomics strategy to identify effective drugs against malaria parasites. A comparative genomics tool available from the TDR Targets Database was used through to select targets expected to be present exclusively in P. falciparum and P. vivax parasites, but absent in humans. Each of the selected targets was then used as a query in the following databases: Drugbank, Therapeutic Target Database and STITCH. The P. falciparum and P. vivax targets were aligned with their predicted homologue targets, using pairwise BLAST, to compare functionally relevant regions. Only those where ≥ 80% overlap was observed between the two sequences for the corresponding drug target were considered for subsequent studies. Thereafter, the drugs identified were submitted to a bibliographic search to find drugs that were never evaluated against malaria parasites in the past. A prediction of active compounds was performed through binary QSAR models. The selected drugs were submitted to in vitro assays using asexual stages of P. falciparum (strains 3D7, chloroquine-sensitive, and W2, multidrug-resistant). Epirubicin displayed potent in vitro activity against the 3D7 strain (IC50 = 140 nM). In addition, the drug was shown to be about twice as active against the W2 resistant strain (IC50 = 69 nM), exhibiting even greater activity than chloroquine. At present, in vitro experiments in sexual stages (ookinete conversion) and in vivo assays with P. berghei and P. chabaudi are being carried out. In conclusion, epirubicin is a good antimalarial drug candidate, although future studies are required to investigate its mechanism of action, potential toxicity, and eventually, to advance in the drug development process.