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Synthesis and biological evaluation of DC-Sign antagonists with oligomeric presentation
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As células dendríticas (DCs) como células apresentadoras de antigénios (APCs) desempenham um papel fundamental no reconhecimento de antigénios e no controlo de uma variedade de respostas do sistema imunitário. Apesar de serem cruciais na defesa contra agentes patogénicos, vários microorganismos usam os receptores DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin) como um "cavalo de Tróia" para escapar ao sistema imunitário, sendo um exemplo o vírus do HIV-1.
Deste modo, a inibição da interação do agente patogénico com os receptores DC-SIGN é um conceito viável para a produção de novos medicamentos anti-infecciosos, evitando não apenas a infecção localizada das DCs mas também a disseminação do agente patogénico.
Monossacarídeos naturais têm uma baixa afinidade para os receptores DC-SIGN e, portanto, a sua utilização como antagonistas da interacção glicano-DC-SIGN torna-se pouco adequada. A concepção de antagonistas glicomiméticos dos receptores DC-SIGN baseia-se principalmente na utilização de ligandos monovalentes de fucose ou de manose com certas características estruturais, a fim de aumentar a sua estabilidade metabólica e a formar interacções adicionais com o sítio de ligação dos receptores DC-SIGN aumentando assim a afinidade de ligação global.
A principal limitação dos ligandos monovalentes é que, mesmo os mais potentes, mal conseguem ultrapassar a avidez de ligação dos ligandos polivalentes, onde uma molécula grande consegue interagir com quatro domínios de reconhecimento de carbohidratos (CRDs) que formam o tetrâmero DC-SIGN, tal como acontece com ligandos naturais como a gp120. Assim, foi planeado sintetizar um antagonista tetravalente dos receptores DC-SIGN através da síntese de um núcleo e quatro cópias de glicomiméticos monovalentes manosilados ligados a esse núcleo.
O tempo do trabalho prático laboratorial foi limitado e num período de 3 meses foi sintetizado o núcleo, bem como um composto glicomimético monovalente. Este último apresentou uma fraca actividade inibitória para o receptor DC-SIGN. Apesar de tudo, o potencial terapêutico dos antagonistas DC-SIGN é enorme e não deve ser negligenciado, pelo que num futuro próximo novas estratégias serão desenvolvidas.
Dendritic cells (DCs) as antigen-presenting cells (APCs) play a critical role in the recognition of many antigens and control an array of responses of the immune system. In spite of being crucial in the defense against pathogens, several microorganisms use DC-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN) as a “Trojan horse” to escape the immune system, such as HIV-1 virus. From this point of view, inhibition of pathogen interaction with DC-SIGN is a plausible concept for new anti-infective drugs, preventing not only localized infection of DCs, but also pathogen dissemination. Native monosaccharides have not only weak affinity to DC-SIGN but also drug-like drawbacks. The design of glycomimetic DC-SIGN antagonists relies mainly on the use of either a monovalent fucose or mannose anchor with further structural features attached, in order to increase their metabolic stability and to form additional interactions with the DC-SIGN binding site which increases global binding affinity. The main limitation of monovalent ligands is that, even the most potent ones, can barely exceed the binding avidity of polyvalent ligands where, like the DC-SIGN native ligands such as gp120, one large molecule interacts with 4 carbohydrate recognition domains (CRDs) of DC-SIGN tetramer or even clusters of tetramers. Therefore we have pursued the plan to create a tetravalent DC-SIGN antagonist by synthesizing a dendron core and four copies of a mannose-based monovalent glycomimetics attached to it via “click chemistry”. The time of the practical work in laboratory was limited and in 3-months period we have synthesized the dendron core and a monovalent glycomimetic compound. This last one showed poor inhibitory affinity to DC-SIGN. In spite of this, the therapeutic potential of DC-SIGN antagonist is so huge that should not be neglected and new strategies will be developed in near future.
Dendritic cells (DCs) as antigen-presenting cells (APCs) play a critical role in the recognition of many antigens and control an array of responses of the immune system. In spite of being crucial in the defense against pathogens, several microorganisms use DC-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN) as a “Trojan horse” to escape the immune system, such as HIV-1 virus. From this point of view, inhibition of pathogen interaction with DC-SIGN is a plausible concept for new anti-infective drugs, preventing not only localized infection of DCs, but also pathogen dissemination. Native monosaccharides have not only weak affinity to DC-SIGN but also drug-like drawbacks. The design of glycomimetic DC-SIGN antagonists relies mainly on the use of either a monovalent fucose or mannose anchor with further structural features attached, in order to increase their metabolic stability and to form additional interactions with the DC-SIGN binding site which increases global binding affinity. The main limitation of monovalent ligands is that, even the most potent ones, can barely exceed the binding avidity of polyvalent ligands where, like the DC-SIGN native ligands such as gp120, one large molecule interacts with 4 carbohydrate recognition domains (CRDs) of DC-SIGN tetramer or even clusters of tetramers. Therefore we have pursued the plan to create a tetravalent DC-SIGN antagonist by synthesizing a dendron core and four copies of a mannose-based monovalent glycomimetics attached to it via “click chemistry”. The time of the practical work in laboratory was limited and in 3-months period we have synthesized the dendron core and a monovalent glycomimetic compound. This last one showed poor inhibitory affinity to DC-SIGN. In spite of this, the therapeutic potential of DC-SIGN antagonist is so huge that should not be neglected and new strategies will be developed in near future.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014
Palavras-chave
Dendritic cells DC-SIGN DC-SIGN antagonists Glycomimetics Mestrado Integrado - 2014