A carregar...
Publicação
Estudo da atividade antimalárica de endoperóxidos
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 9.65 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
Resumo
A malária, umas das principais doenças infeciosas globais, e causada por parasitas do
género Plasmodium spp. é transmitida por mosquitos fêmea do género Anopheles spp.
A resistência de Plasmodium falciparum aos tratamentos antimaláricos tem
impulsionado a busca por novas soluções terapêuticas.
O presente trabalho focou-se na avaliação da atividade antimalárica de novos
endoperóxidos sintéticos contra estirpes resistentes e sensíveis de P. falciparum.
Utilizando técnicas in vitro (citometria de fluxo), os compostos foram testados quanto
à sua capacidade de inibir a proliferação dos parasitas, com a determinação dos
valores de IC50 servindo como medida de atividade. O estudo abrangeu também a
análise da atividade estádio-específica dos compostos, verificando a sua eficácia em
diferentes fases do ciclo do parasita.
Todos os 7 compostos testados, apresentaram atividade sub-micromolar (IC50 < 1μM)
contra ambas as estirpes 3D7HT-GFP (sensível) e IPC5202 (resistente). Destes, 6
exibiram IC50 <100 nM, variando entre 2,19 - 31,95 nM na estirpe sensível e 2,44 -
58,08 nM na resistente. Um dos compostos, o trioxolano AS04, foi encapsulado numa
partícula formada por cucurbitilos, o conjunto AS04+partícula foi designado AG521.
A diferença de atividade entre AS04 e AG521 foi pouco apreciável sendo que o IC50
se manteve abaixo dos 100 nM, e no range de atividades in vitro demonstrada por
outros endoperóxidos em uso clínico como a DHA, o arteméter ou o artesunato.
Os resultados indicam que os endoperóxidos testados mantêm atividade substancial
contra as estirpes de P. falciparum, suscetíveis e resistentes a derivados da
artemisinina, sugerindo que estes compostos possuem promissor potencial como
antimaláricos.
Abstract Malaria, one of the main global infectious diseases, is caused by parasites of the genus Plasmodium spp. transmitted by female mosquitoes of the genus Anopheles spp. The resistance of Plasmodium falciparum to antimalarial treatments has driven the search for new therapeutic solutions. The present work focuses on the evaluation of the antimalarial activity of new synthetic endoperoxides, against resistant and sensitive strains of P. falciparum. Using in vitro techniques (fow cytometry), the compounds were tested for their ability to inhibit parasite proliferation, with the determination of IC50 values as a measure of activity. The study also covered the analysis of the stage-specific activity of the compounds, verifying their effectiveness in different phases of the parasite life cycle. All 7 compounds tested, showed sub-micromolar activity (IC50 < 1μM) against both strains 3D7HT-GFP (sensitive) and IPC5202 (resistant). Of these, 6 exhibited IC50 <100 nM, ranging between 2.19 - 31.95 nM in for the sensitive strain and 2.44 - 58.08 nM for the resistant strain. One of the compounds, trioxolane AS04, was encapsulated in a particle formed by cucurbiturils, the AS04+particle was designated AG521. The difference in activity between AS04 and AG521 was low, with the IC50 remaining below 100 nM, and within the range of in vitro activities demonstrated by other endoperoxides in clinical use, such as DHA, artemether or artesunate. The results indicate that the endoperoxides tested, had substantial activity against both susceptible and resistant P. falciparum strains to artemisinin derivatives, suggesting that these compounds have promising potential as antimalarials.
Abstract Malaria, one of the main global infectious diseases, is caused by parasites of the genus Plasmodium spp. transmitted by female mosquitoes of the genus Anopheles spp. The resistance of Plasmodium falciparum to antimalarial treatments has driven the search for new therapeutic solutions. The present work focuses on the evaluation of the antimalarial activity of new synthetic endoperoxides, against resistant and sensitive strains of P. falciparum. Using in vitro techniques (fow cytometry), the compounds were tested for their ability to inhibit parasite proliferation, with the determination of IC50 values as a measure of activity. The study also covered the analysis of the stage-specific activity of the compounds, verifying their effectiveness in different phases of the parasite life cycle. All 7 compounds tested, showed sub-micromolar activity (IC50 < 1μM) against both strains 3D7HT-GFP (sensitive) and IPC5202 (resistant). Of these, 6 exhibited IC50 <100 nM, ranging between 2.19 - 31.95 nM in for the sensitive strain and 2.44 - 58.08 nM for the resistant strain. One of the compounds, trioxolane AS04, was encapsulated in a particle formed by cucurbiturils, the AS04+particle was designated AG521. The difference in activity between AS04 and AG521 was low, with the IC50 remaining below 100 nM, and within the range of in vitro activities demonstrated by other endoperoxides in clinical use, such as DHA, artemether or artesunate. The results indicate that the endoperoxides tested, had substantial activity against both susceptible and resistant P. falciparum strains to artemisinin derivatives, suggesting that these compounds have promising potential as antimalarials.
Descrição
Palavras-chave
Ciências biomédicas Biologia molecular Saúde tropical e internacional