Estudo do peptídeo lítico Hecate e sua conjugação com ácido gálico: atividade contra o carcinoma cervical humano, mecanismo de ação e toxicidade
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Data
2016-03-11
Autores
Sanches, Paulo Ricardo da Silva [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A síntese de peptídeos em fase sólida mostra-se como uma importante ferramenta para a modelagem de macromoléculas biológicas, sendo algumas de interesse quimioterápico. Desde que foi descrita pela primeira vez, esta técnica tem possibilitado a síntese de inúmeros peptídeos e o estudo aprofundado dessas moléculas. Peptídeos líticos apresentam-se como novas moléculas promissoras contra neoplasias, sendo seu mecanismo de ação ainda obscuro. O câncer é uma doença causada por fatores que provocam o desenvolvimento anormal de células do organismo. Estas células tendem a ser agressivas e incontroláveis, determinando a formação de tumores. O câncer cervical é um dos mais comuns, afetando principalmente regiões pouco desenvolvidas. Infecções pelo vírus HPV, tabagismo, falta de higiene pessoal e relações sexuais sem o uso de preservativos são as principais causas pelo aparecimento da doença. O HPV é um vírus não envelopado, de dupla fita de DNA circular e que promove infecção em células basais em divisão do epitélio. Este trabalho descreve a síntese, purificação e caracterização do peptídeo lítico Hecate (FALALKALKKALKKLKKALKKAL) e do conjugado ácido gálico-Hecate (AG-FALALKALKKALKKLKKALKKAL). Estas moléculas foram utilizadas na busca de novas terapias contra o câncer cervical causado por infecção viral e no entendimento de seu modo de ação. Os resultados mostraram que o peptídeo apresenta alta potencialidade contra o câncer cervical, mas o acoplamento do ácido gálico na sua posição amino terminal, além de diminuir a potencialidade contra o câncer, aumentou sua atividade hemolítica. Estas diferenças estão diretamente relacionadas com a diferença de carga dos dois compostos, a diferente composição lipídica das células e a estrutura secundária dos compostos.
The solid phase peptide synthesis is shown as an important tool for modeling of biological macromolecules, and some chemotherapeutic interest. Since it was first described this technique has made possible the synthesis of numerous peptides and careful study of these molecules. Lytic peptides are presented as promising new molecules against cancer, and the action mechanism is still unclear. Cancer is a disease caused by factors that cause abnormal development of the body's cells. These cells tend to be aggressive and uncontrollable, causing tumor formation. Cervical cancer is the most common, affecting mainly underdeveloped regions. Infection by the HPV virus, smoking, lack of personal hygiene and sex without protection are the main causes for the appearance of the disease. The HPV virus is a non-enveloped virus with circular double-stranded DNA and promotes infection in the dividing basal cells of the epithelium. This work describes the synthesis, purification and characterization of the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and conjugate gallic acid-Hecate (GA-FALALKALKKALKKLKKALKKAL). These molecules were used in the search for new therapies against cervical cancer caused by viral infection and understanding of their mode of action. The results showed that the peptide has a high potential against cervical cancer, but the coupling of gallic acid in its amino terminal position reduces the potential of peptide for cancer and increases his hemolytic activity. These differences are directly related to the charge difference of the two compounds, the different lipid composition of cells and the secondary structure of the compounds.
The solid phase peptide synthesis is shown as an important tool for modeling of biological macromolecules, and some chemotherapeutic interest. Since it was first described this technique has made possible the synthesis of numerous peptides and careful study of these molecules. Lytic peptides are presented as promising new molecules against cancer, and the action mechanism is still unclear. Cancer is a disease caused by factors that cause abnormal development of the body's cells. These cells tend to be aggressive and uncontrollable, causing tumor formation. Cervical cancer is the most common, affecting mainly underdeveloped regions. Infection by the HPV virus, smoking, lack of personal hygiene and sex without protection are the main causes for the appearance of the disease. The HPV virus is a non-enveloped virus with circular double-stranded DNA and promotes infection in the dividing basal cells of the epithelium. This work describes the synthesis, purification and characterization of the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and conjugate gallic acid-Hecate (GA-FALALKALKKALKKLKKALKKAL). These molecules were used in the search for new therapies against cervical cancer caused by viral infection and understanding of their mode of action. The results showed that the peptide has a high potential against cervical cancer, but the coupling of gallic acid in its amino terminal position reduces the potential of peptide for cancer and increases his hemolytic activity. These differences are directly related to the charge difference of the two compounds, the different lipid composition of cells and the secondary structure of the compounds.
Descrição
Palavras-chave
Câncer cervical, Peptídeos líticos, Bioconjugados, Hecate, Ácido gálico, Mecanismo de ação