Síntese e avaliação biológica de novas saponinas imunoactivas
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Data
2006
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Edições Universitárias Lusófonas
Resumo
A saponina QS21 é uma saponina natural extraída da casca das árvores endémicas da América do Sul conhecida por
desempenhar um papel importante como adjuvante de vacinas. O objectivo deste estudo foi determinar se os
análogos sintéticos mais simples da QS-21 podem induzir respostas imunes com igual vantagem. Para isso, foram
desenhados e sintetizados os ácidos 3-ß -O-(ß -D-xilopiranosil)-(1? 3)-[(ß -D-galactopiranosil)-(1? 2)]-6-ß -Dglucurónicos
derivados de colestanol e amirina 1 e 2, respectivamente, ligando primeiro resíduos glucósidos ao
terpeno e estendendo depois a cadeia de açúcar. A sua actividade adjuvante foi avaliada in vitro através da secreção de
mediadores pró-inflamatórios de células IL-6 e IL-1, TNF-a e NO e os níveis de IgG no soro depois da estimulação
in vivo das células apresentadoras de antigénio (APCs) . Os compostos 1 e 2 foram bastante mais citotóxicos para as
células tumorais J744A.1 de murino do que a QS21 e mostraram menos actividade hemolítica indesejada nos
glóbulos vermelhos do que a QS-21, mas não induziram respostas citotóxicas CD8 fortes após uma única injecção, o
que aconteceu no processo de imunização com ovalbumina e QS-21. Apesar de os análogos 1 e 2 apresentarem boa
actividade adjuvante in vitro, a ausência do grupo aldeído e da cadeia acilo é provavelmente o que afecta
negativamente as propriedades das saponinas simplificadas para induzir células T citotóxicas activas em ratinhos.
QS21 is a natural saponin extracted with water from the bark of endemic trees of South America which has been shown to play a key role as vaccine adjuvant. The aim of this study was to determine if simpler synthetic analogues of QS-21 could induce similar advantageous immune responses. For this purpose we designed and synthesized both the cholestanyl- and amirinyl-3-ß -O-(ß -D-xylopyranosyl)-(1? 3)-[(ß -D-galactopyranosyl)-(1? 2)]-6-ß -D-glucuronic acid 1 and 2, respectively, by first attaching the glucoside residues to the terpene and then extending the sugar chain. The secretion of the pro-inflammatory cell mediators IL-6 and IL-1, TNF-a and NO and the IgG serum levels after in vivo stimulation of APCs with 1 and 2, were used to assess their adjuvant activity in vitro. Compounds 1 and 2 were stronger cytotoxic for murine J744A.1 tumor cells than QS21 and showed less undesired hemolytic activity on red blood cells than QS-21, but did not induce strong cytotoxic CD8 responses after a single injection, while immunization with ovalbumin and QS-21 did. Although synthetic analogues 1 and 2 show good adjuvant activity in vitro it is probably the lack of the aldehyde group and the acyl chain that negatively affects the simplified saponins properties to induce active cytotoxic T cells in mice.
QS21 is a natural saponin extracted with water from the bark of endemic trees of South America which has been shown to play a key role as vaccine adjuvant. The aim of this study was to determine if simpler synthetic analogues of QS-21 could induce similar advantageous immune responses. For this purpose we designed and synthesized both the cholestanyl- and amirinyl-3-ß -O-(ß -D-xylopyranosyl)-(1? 3)-[(ß -D-galactopyranosyl)-(1? 2)]-6-ß -D-glucuronic acid 1 and 2, respectively, by first attaching the glucoside residues to the terpene and then extending the sugar chain. The secretion of the pro-inflammatory cell mediators IL-6 and IL-1, TNF-a and NO and the IgG serum levels after in vivo stimulation of APCs with 1 and 2, were used to assess their adjuvant activity in vitro. Compounds 1 and 2 were stronger cytotoxic for murine J744A.1 tumor cells than QS21 and showed less undesired hemolytic activity on red blood cells than QS-21, but did not induce strong cytotoxic CD8 responses after a single injection, while immunization with ovalbumin and QS-21 did. Although synthetic analogues 1 and 2 show good adjuvant activity in vitro it is probably the lack of the aldehyde group and the acyl chain that negatively affects the simplified saponins properties to induce active cytotoxic T cells in mice.
Descrição
Revista Lusófona de Ciências e Tecnologias da Saúde
Palavras-chave
MEDICINA, IMUNOLOGIA, VACINAÇÃO, ESTUDOS DE CASO, PLANTAS, MEDICINE, IMMUNOLOGY, VACCINATION, CASE STUDIES, PLANTS