Modelagem molecular e síntese de inibidores de histona deacetilase-3 (HDAC-3), planejados como como agentes reversores de latência do HIV
Data
2023-08-31
Autores
Fernandes, Lívia da Rocha
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ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
Ainda que mais de 40 anos da descoberta do vírus da imunodeficiência humana (HIV), tenham se passado, e avanços significativos tenham sido conquistados, a exemplo do aumento na expectativa de vida dos pacientes vivendo com HIV, a infecção ainda se mantem incurável. Em 2019, estimou-se que o número de pessoas infectadas era de cerca 37,9 milhões no mundo, das quais 24,5 milhões tinham acesso a terapia antirretroviral (TARV). A TARV reduz efetivamente a carga viral, mas não elimina o vírus, que permanece latente em células T CD4+ podendo ser reativado com a interrupção do tratamento. Nesse contexto, abordagens terapêuticas visando a cura funcional são urgentes. Dentre essas, a estratégia “kick-and-kill”, visa esgotar o reservatório viral pela reativação do HIV latente por agentes reversores latência (ARL) (kick), e eliminação de células infectadas por efeitos citopáticos, resposta imunológica ou associação a compostos que induzam a eliminação do vírus reativado (kill). A hipótese é que a combinação dessa nova estratégia associada ao tratamento continuo com a TARV impeça que o vírus reativado consiga infectar células saudáveis, podendo ser um novo caminho a ser explorado para a eliminação dos reservatórios celulares latentes do vírus. A perpetuação do vírus nestes reservatórios e em baixo estado de replicação é um dos grandes desafios para sua completa eliminação a fim de atingir a cura funcional. Dentre os reservatórios de HIV, os linfonodos constituem o exemplo mais conhecido, por conterem grande quantidade de linfócitos T CD4+ e outras células imunes. Dentre os ARL, aqueles que atuam por mecanismos epigenéticos parecem ser promissores, dos quais se destacam os inibidores de histona deacetilase (HDAC). Dessa maneira, este estudo visa planejar e sintetizar novos potenciais inibidores de histona deacetilase-3 como candidatos a ARL para o HIV, direcionados aos linfonodos por meio da estratégia da latenciação de fármacos. Assim, por meio de estudos de modelagem molecular foram planejadas uma série de compostos, que foram divididos em duas séries, a saber: série A (cap amina), e série B (cap metil-amina). No total, foram sintetizados 21 compostos, dos quais 13 são intermediários; e 6 são produtos finais. Destes finais, 2 são pertencentes a série A, e 4 pertencentes a série B. Todos os compostos foram caracterizados por métodos analíticos como ressonância magnética nuclear (RMN) e infravermelho (IV). Os produtos finais foram obtidos em rendimentos globais que variaram de 2-15% (2% (3b); 3% (2a); 6% (4b); 10% (19); 14% (1a); 15% (23)).
Although more than 40 years have passed since the discovery of the human immunodeficiency virus (HIV), and significant advances have been achieved, such as the increase in life expectancy of patients living with HIV, the infection remains incurable. In 2019, the number of infected people was estimated to be around 37.9 million worldwide, of which 24.5 million had access to antiretroviral therapy (ART). ART effectively reduces viral load, but does not eliminate the virus, which remains latent in CD4+ T cells and can be reactivated when treatment is interrupted. In this context, therapeutic approaches aiming at a functional cure are urgently needed. Among these, the "kick-and-kill" strategy aims to deplete the latent viral reservoir by reactivating latent HIV by latency-reversing agents (LRA) (kick), and eliminating infected cells by cytopathic effects, immune response, or association with compounds that induce elimination of the reactivated virus (kill). The hypothesis is that the combination of this new strategy associated with continuous treatment with ART prevents the reactivated virus from infecting healthy cells and may be a new path to be explored for the elimination of latent cellular reservoirs of the virus. The perpetuation of the virus in these reservoirs and in a low state of replication is one of the major challenges for its complete elimination in order to achieve a functional cure. Among the HIV reservoirs, the lymph nodes are the best-known example, because they contain large numbers of CD4+ T lymphocytes and other immune cells. Among the ARLs, those that act through epigenetic mechanisms seem to be promising, of which the histone deacetylase inhibitors (HDAC) stand out. Thus, this study aims to design and synthesize new potential histone deacetylase-3 inhibitors as candidate ARLs for HIV, targeting lymph nodes through the strategy of drug latentiation. Thus, through molecular modeling studies, a series of compounds were planned, which were divided into two series, namely: series A (cap amine), and series B (cap methyl-amine). In total, 21 compounds were synthesized, of which 13 are intermediates; and 6 are final products. Of these endings, 2 belong to the A series, and 4 belong to the B series. All compounds were characterized by analytical methods such as nuclear magnetic resonance (NMR) and infrared (IR). Final products were obtained in overall yields ranging from 2-15% (2% (3b); 3% (2a); 6% (4b); 10% (19); 14% (1a); 15% (23)).
Although more than 40 years have passed since the discovery of the human immunodeficiency virus (HIV), and significant advances have been achieved, such as the increase in life expectancy of patients living with HIV, the infection remains incurable. In 2019, the number of infected people was estimated to be around 37.9 million worldwide, of which 24.5 million had access to antiretroviral therapy (ART). ART effectively reduces viral load, but does not eliminate the virus, which remains latent in CD4+ T cells and can be reactivated when treatment is interrupted. In this context, therapeutic approaches aiming at a functional cure are urgently needed. Among these, the "kick-and-kill" strategy aims to deplete the latent viral reservoir by reactivating latent HIV by latency-reversing agents (LRA) (kick), and eliminating infected cells by cytopathic effects, immune response, or association with compounds that induce elimination of the reactivated virus (kill). The hypothesis is that the combination of this new strategy associated with continuous treatment with ART prevents the reactivated virus from infecting healthy cells and may be a new path to be explored for the elimination of latent cellular reservoirs of the virus. The perpetuation of the virus in these reservoirs and in a low state of replication is one of the major challenges for its complete elimination in order to achieve a functional cure. Among the HIV reservoirs, the lymph nodes are the best-known example, because they contain large numbers of CD4+ T lymphocytes and other immune cells. Among the ARLs, those that act through epigenetic mechanisms seem to be promising, of which the histone deacetylase inhibitors (HDAC) stand out. Thus, this study aims to design and synthesize new potential histone deacetylase-3 inhibitors as candidate ARLs for HIV, targeting lymph nodes through the strategy of drug latentiation. Thus, through molecular modeling studies, a series of compounds were planned, which were divided into two series, namely: series A (cap amine), and series B (cap methyl-amine). In total, 21 compounds were synthesized, of which 13 are intermediates; and 6 are final products. Of these endings, 2 belong to the A series, and 4 belong to the B series. All compounds were characterized by analytical methods such as nuclear magnetic resonance (NMR) and infrared (IR). Final products were obtained in overall yields ranging from 2-15% (2% (3b); 3% (2a); 6% (4b); 10% (19); 14% (1a); 15% (23)).
Descrição
Palavras-chave
HIV, Agentes Reversores de Latência, pró-fármaco, inibidor de HDAC-3, sistema linfático, reservatório HIV, cura funcional