Síntese de inibidores duais como agentes reversores de latencia para HIV
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Data
2021-12-17
Autores
Gerlack, Max
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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 ou AIDS em inglês). Embora altamente efetivo na redução da carga viral, o tratamento com a terapia antirretroviral (TARV) não promove a eliminação do vírus, uma vez que o HIV permanece em estado latente nos linfócitos T CD4+ de memória, sendo reativado com a interrupção do tratamento. Essas células latentes não expressam as proteínas virais e, portanto, permanecem indetectáveis pelo sistema imunológico. A fim de eliminar o vírus dos reservatórios celulares, e atingir a ‘cura funcional’ foi planejada a estratégia ‘kick and kill’. Essa abordagem visa o uso de agentes reversores de latência, capazes de reativar o HIV em estado latente e levar novamente a replicação viral. Duas classes investigadas nessa abordagem são os inibidores de histona deacetilase (HDAC) e os inibidores de bromodomínio 4 (BRD4). Assim visando a reativação desses reservatórios, devido sua importância para o processo de latência viral, este trabalho teve por objetivo sintetizar e caracterizar moléculas que apresentaram boa seletividade para a inibição das HDAC classe I (HADC 1, 2 e 3) e BRD4, sendo que um dos compostos sintetizados apresentou capacidade de inibição de 92% para HADC 1 e também 12% de inibição para BRD4 em ensaios enzimáticos.
The human immunodeficiency virus (HIV) is the cause of the acquired immunodeficiency syndrome (AIDS or AIDS in English). Still highly effective in reducing viral load, treatment with antiretroviral therapy (ART) does not promote the elimination of the virus, since HIV remains in a latent state in memory CD4+ T lymphocytes, being reactivated with the interruption of treatment. These latent cells do not express as viral proteins and therefore remain undetectable by the immune system. In order to eliminate the virus from the cell reservoirs, and achieve the "functional cure" the "kick and kill" strategy was planned. This approach aims at the use of latency reversing agents, capable of reactivating HIV in a latent state and leading to viral replication again. Two classes investigated in this approach are histone deacetylase inhibitors (HDAC) and bromodomain 4 inhibitors (BRD4). Therefore, the reactivation of these reservoirs, due to their importance for the viral latency process, this work aimed to synthesize and characterize molecules that dissipate good selectivity for inhibiting HDAC class I (HADC 1, 2 and 3) and BRD4, being that one of the synthesized compounds has 92% inhibition capacity for HADC 1 and also 12% inhibition for BRD4 in enzymatic assays
The human immunodeficiency virus (HIV) is the cause of the acquired immunodeficiency syndrome (AIDS or AIDS in English). Still highly effective in reducing viral load, treatment with antiretroviral therapy (ART) does not promote the elimination of the virus, since HIV remains in a latent state in memory CD4+ T lymphocytes, being reactivated with the interruption of treatment. These latent cells do not express as viral proteins and therefore remain undetectable by the immune system. In order to eliminate the virus from the cell reservoirs, and achieve the "functional cure" the "kick and kill" strategy was planned. This approach aims at the use of latency reversing agents, capable of reactivating HIV in a latent state and leading to viral replication again. Two classes investigated in this approach are histone deacetylase inhibitors (HDAC) and bromodomain 4 inhibitors (BRD4). Therefore, the reactivation of these reservoirs, due to their importance for the viral latency process, this work aimed to synthesize and characterize molecules that dissipate good selectivity for inhibiting HDAC class I (HADC 1, 2 and 3) and BRD4, being that one of the synthesized compounds has 92% inhibition capacity for HADC 1 and also 12% inhibition for BRD4 in enzymatic assays
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Palavras-chave
Epigenética, novos fármacos, inibidores de bromodomínio, inibidores de histona deacetilase, Epigenetics, New drugs, bromodomain inhibitors, Histone Deacetylase Inhibitors., HIV