Planejamento, síntese e avaliação farmacológica de agentes reversores de latência para eliminação de reservatórios celulares do HIV
Data
2020-03-10
Autores
Lopes, Juliana Romano
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O vírus da imunodeficiência humana (HIV) é o causador da síndrome da imunodeficiência adquirida (SIDA). Estimativas para o ano de 2018 apontavam que cerca 37,9 milhões de pessoas viviam com HIV no mundo naquele ano. Até o presente momento, a infecção pelo vírus HIV-1 se mantém incurável. A terapia antirretroviral altamente ativa (TARV), embora altamente efetiva na redução da carga viral, não implica na eliminação do vírus, uma vez que o HIV permanece em um estado latente em células T CD4+ e pode ser reativado com a interrupção do tratamento. A estratégia “kick-and-kill” ou “shock-and-kill” visa induzir a replicação do vírus nos reservatórios latentes por meio de agentes reversores de latência (LARs). Assim, as células infectadas poderiam ser eliminadas através de efeitos citopáticos decorrentes da infecção e da resposta imunológica, ou por meio da associação de compostos que induzam a eliminação do vírus reativado (“kill agents”). A combinação dessa nova estratégia com a TARV impede que o vírus reativado consiga infectar células saudáveis, podendo ser um novo caminho a ser explorado para a eliminação dos reservatórios latentes de HIV. Inibidores de histona deacetilase (HDAC) e bromodomínios (BRD) têm sido relatados como promissores agentes reversores de latência. Neste trabalho, utilizando ferramentas de modificação molecular, oito compostos promissores foram planejados. Dos oito, seis compostos finais foram sintetizados e avaliados frente HDAC classe I e BRD4, destacando-se dois mais promissores por sua atividade dual HDAC/BRD4 que serão posteriormente avaliados dentro da estratégia kick-and-kill. Os resultados deste trabalho podem levar ao desenvolvimento de novos agentes reversores de latência e contribuir com a continuidade dos estudos da estratégia.
The human imunnodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Estimates for the 2018 year suggested that about 37,9 millions of people lived with HIV worldwide. Until the present moment, the HIV infection remains incurable. The continuous treatment with Highly Active Antiretroviral Therapy (HAART), although highly effective in reduction of viral load, does not imply in the elimination of virus, once the virus HIV remains in a latent state in CD4+ T cells and can be reactivated after interruption of the treatment. The “kick-and-kill” or “shock-and-kill” strategy aims to induce the replication of virus in the latent reservoirs by Latency Reversal Agents (LRAs), for posterior elimination of these infected cells through cytopathic effects due to infection and host immunological response, or through association with compounds that induce the elimination of reactivated virus (kill agents). The combination of this new strategy with HAART prevents the reactivated virus to infected healthy cells and could be a new approach to exaust and eliminate latent reservoirs of HIV. Histone deacetylase inhibitors (HDACi) and bromodomain inhibitors (BRDi) have been related as promising LRAs. In this work, using molecular modification tools, eight promising compounds were planned. Of the eight, six final compounds were synthesized and evaluated against HDAC class I and BRD4, with two more promising for their dual HDAC/BRD4 activity, which will later be evaluated within the kick-and-kill strategy. The results of this work can lead to the development of new latency reversal agents and contribute to the continuity of the strategy studies.
The human imunnodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Estimates for the 2018 year suggested that about 37,9 millions of people lived with HIV worldwide. Until the present moment, the HIV infection remains incurable. The continuous treatment with Highly Active Antiretroviral Therapy (HAART), although highly effective in reduction of viral load, does not imply in the elimination of virus, once the virus HIV remains in a latent state in CD4+ T cells and can be reactivated after interruption of the treatment. The “kick-and-kill” or “shock-and-kill” strategy aims to induce the replication of virus in the latent reservoirs by Latency Reversal Agents (LRAs), for posterior elimination of these infected cells through cytopathic effects due to infection and host immunological response, or through association with compounds that induce the elimination of reactivated virus (kill agents). The combination of this new strategy with HAART prevents the reactivated virus to infected healthy cells and could be a new approach to exaust and eliminate latent reservoirs of HIV. Histone deacetylase inhibitors (HDACi) and bromodomain inhibitors (BRDi) have been related as promising LRAs. In this work, using molecular modification tools, eight promising compounds were planned. Of the eight, six final compounds were synthesized and evaluated against HDAC class I and BRD4, with two more promising for their dual HDAC/BRD4 activity, which will later be evaluated within the kick-and-kill strategy. The results of this work can lead to the development of new latency reversal agents and contribute to the continuity of the strategy studies.
Descrição
Palavras-chave
HIV, Kick and Kill, Agentes reversores de latência