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Evaluation of antiviral drugs against BK polyomavirus
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O poliomavírus BK é um vírus de DNA pertencente à família Polyomaviridae. A infeção primária é normalmente assintomática, após a qual o vírus estabelece uma infeção persistente maioritariamente nas células epiteliais do trato urinário e do rim. Em indivíduos imunocompetentes o vírus permanece clinicamente silencioso durante toda a vida do hospedeiro. No entanto, a imunossupressão pode conduzir à reativação do vírus latente, sendo uma das principais complicações desta reativação a nefropatia associada a poliomavírus em transplantados renais. O desenvolvimento de imunossupressores cada vez mais potentes tem aumentado a incidência da nefropatia nestes doentes e atualmente, não existindo nenhum antiviral que possa ser utilizado de forma eficaz e segura contra este vírus, a abordagem clínica consiste na redução do tratamento imunossupressor de modo a prevenir o desenvolvimento da nefropatia. Neste contexto, o desenvolvimento e a procura de antivirais que consigam eficazmente impedir a replicação do poliomavírus BK têm assumido um grande interesse clínico. O principal objetivo deste projeto consistiu no estudo da eficácia de dois compostos - NA-17 e TN-18 - contra a replicação do poliomavírus BK em células epiteliais tubulares proximais renais imortalizadas com hTERT (RPTEC/TERT1), uma linha celular imortalizada de um dos maiores alvos celulares do vírus in vivo. Os resultados mostraram uma inibição da infeção pelo poliomavírus BK, tendo sido estimadas as concentrações responsáveis por uma inibição de 50% da infeção de 190 μM e 682 μM para o NA-17 e o TN-18, respetivamente. O tratamento com as concentrações mais elevadas testadas para ambos os compostos foi responsável por uma redução da carga extracelular de DNA viral, assim como na redução de libertação de novas partículas virais infeciosas. De um modo geral, os resultados mostram um efeito antiviral moderado de ambos os compostos contra o poliomavírus BK, mostrando que teriam um efeito limitado no tratamento desta infeção in vivo. A continuação da investigação nesta área é necessária para o desenvolvimento de um tratamento eficaz da infeção pelo poliomavírus BK e para a melhoria do prognóstico nos transplantados renais que desenvolvem nefropatia como resultado da reativação desta infeção.
BK polyomavirus (BKPyV) is a DNA virus belonging to the Polyomaviridae family. BKPyV is considered ubiquitous among the population, and primary infection usually occurs during early childhood. This primary infection is usually asymptomatic, following which the virus establishes a lifelong persistent infection mainly on epithelial cells of the urinary tract and the kidney. In immunocompetent individuals the virus remains clinically silent throughout the life of the host. Immunosuppression, however, can lead to reactivation of the latent infection. In such conditions, one of the major clinical complications of BKPyV reactivation is polyomavirus-associated nephropathy (PyVAN) in kidney transplant recipients. The development of more potent immunosuppressant drugs has increased the incidence rate of PyVAN in these patients and to date, because a specific and safe antiviral drug against BKPyV is still lacking, the mainstay approach to avoid PyVAN development and the possibility of graft loss is to reduce the immunosuppressive treatment. In this context, the development and search for antiviral drugs that can efficiently stop BKPyV replication has become of great clinical interest. This project focused on studying the efficacy of two drugs - NA-17 and TN-18 - against BKPyV replication in hTERT immortalized human renal proximal tubular epithelial cells (RPTEC/TERT1), an immortalized cell line of the major target cells of the virus in vivo. Results showed an inhibition of BKPyV infection with both NA-17 and TN-18, having been estimated effective concentration 50% (EC50) values of 190 μM and 682 μM, respectively. Treatment of BKPyV-infected RPTEC/TERT1 with the highest concentrations tested for both drugs was responsible for a decrease of the extracellular BKPyV DNA load, that although discrete, corresponded also with an inhibition of the release of infectious progeny. Overall our results show a moderate antiviral effect against BKPyV for both drugs, making us believe that they would have only a limited effect on treating this infection in vivo. Further research in this area is needed to develop an efficient treatment against BKPyV infection and to improve disease outcomes in kidney transplant recipients that develop PyVAN as a result of BKPyV infection reactivation.
BK polyomavirus (BKPyV) is a DNA virus belonging to the Polyomaviridae family. BKPyV is considered ubiquitous among the population, and primary infection usually occurs during early childhood. This primary infection is usually asymptomatic, following which the virus establishes a lifelong persistent infection mainly on epithelial cells of the urinary tract and the kidney. In immunocompetent individuals the virus remains clinically silent throughout the life of the host. Immunosuppression, however, can lead to reactivation of the latent infection. In such conditions, one of the major clinical complications of BKPyV reactivation is polyomavirus-associated nephropathy (PyVAN) in kidney transplant recipients. The development of more potent immunosuppressant drugs has increased the incidence rate of PyVAN in these patients and to date, because a specific and safe antiviral drug against BKPyV is still lacking, the mainstay approach to avoid PyVAN development and the possibility of graft loss is to reduce the immunosuppressive treatment. In this context, the development and search for antiviral drugs that can efficiently stop BKPyV replication has become of great clinical interest. This project focused on studying the efficacy of two drugs - NA-17 and TN-18 - against BKPyV replication in hTERT immortalized human renal proximal tubular epithelial cells (RPTEC/TERT1), an immortalized cell line of the major target cells of the virus in vivo. Results showed an inhibition of BKPyV infection with both NA-17 and TN-18, having been estimated effective concentration 50% (EC50) values of 190 μM and 682 μM, respectively. Treatment of BKPyV-infected RPTEC/TERT1 with the highest concentrations tested for both drugs was responsible for a decrease of the extracellular BKPyV DNA load, that although discrete, corresponded also with an inhibition of the release of infectious progeny. Overall our results show a moderate antiviral effect against BKPyV for both drugs, making us believe that they would have only a limited effect on treating this infection in vivo. Further research in this area is needed to develop an efficient treatment against BKPyV infection and to improve disease outcomes in kidney transplant recipients that develop PyVAN as a result of BKPyV infection reactivation.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Palavras-chave
Poliomavírus Poliomavírus BK Antiviral Nefropatia Transplante renal Mestrado Integrado - 2019