Érica Araújo Mendes1, Denise Regina Bairros de Pilger2, Ana Catharina de Seixas Santos Nastri3, Fernanda de Mello Malta4, Bruno Dos Santos Pascoalino1, Luiz Augusto Carneiro D'Albuquerque4, Andrea Balan1, Lucio Holanda Gondim de Freitas2, Edison Luis Durigon1, Flair José Carrilho4, João Renato Rebello Pinho5. 1. Department of Microbiology, University of São Paulo Biomedical Sciences Institute, São Paulo, Brazil. 2. Department of Microbiology, University of São Paulo Biomedical Sciences Institute, São Paulo, Brazil; Butantan Institute, São Paulo, Brazil. 3. Department of Parasitic and Infectious Diseases, University of São Paulo School of Medicine, São Paulo, Brazil; LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil. 4. LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil. 5. Hospital Israelita Albert Einstein, São Paulo, Brazil; LIM-03, Central Laboratories Division, Clinics Hospital, São Paulo School of Medicine, University of São Paulo, São Paulo, Brazil; LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil. Electronic address: jrrpinho@usp.br.
Abstract
INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) are very efficient in inhibiting hepatitis C virus and might be used to treat infections caused by other flaviviruses whose worldwide detection has recently increased. The aim of this study was to verify the efficacy of DAAs in inhibiting yellow fever virus (YFV) by using drug repositioning (a methodology applied in the pharmaceutical industry to identify new uses for approved drugs). MATERIALS AND METHODS: Three DAAs were evaluated: daclatasvir, sofosbuvir and ledipasvir or their combinations. For in vitro assays, the drugs were diluted in 100% dimethyl sulfoxide. Vaccine strain 17D and a 17D strain expressing the reporter fluorescent protein were used in the assays. A fast and reliable cell-based screening assay using Vero cells or Huh-7 cells (a hepatocyte-derived carcinoma ell line) was carried out. Two patients who acquired yellow fever virus with acute liver failure were treated with sofosbuvir for one week as a compassionate use. RESULTS: Using a high-content screening assay, we verified that sofosbuvir presented the best antiviral activity against YFV. Moreover, after an off-label treatment with sofosbuvir, the two female patients diagnosed with yellow fever infection displayed a reduction in blood viremia and an improvement in the course of the disease, which was observed in the laboratory medical parameters related to disease evolution. CONCLUSIONS: Sofosbuvir may be used as an option for treatment against YFV until other drugs are identified and approved for human use. These results offer insights into the role of nonstructural protein 5 (NS5) in YFV inhibition and suggest that nonstructural proteins may be explored as drug targets for YFV treatment.
INTRODUCTION AND OBJECTIVES: Direct antiviral agents (DAAs) are very efficient in inhibiting hepatitis C virus and might be used to treat infections caused by other flaviviruses whose worldwide detection has recently increased. The aim of this study was to verify the efficacy of DAAs in inhibiting yellow fever virus (YFV) by using drug repositioning (a methodology applied in the pharmaceutical industry to identify new uses for approved drugs). MATERIALS AND METHODS: Three DAAs were evaluated: daclatasvir, sofosbuvir and ledipasvir or their combinations. For in vitro assays, the drugs were diluted in 100% dimethyl sulfoxide. Vaccine strain 17D and a 17D strain expressing the reporter fluorescent protein were used in the assays. A fast and reliable cell-based screening assay using Vero cells or Huh-7 cells (a hepatocyte-derived carcinoma ell line) was carried out. Two patients who acquired yellow fever virus with acute liver failure were treated with sofosbuvir for one week as a compassionate use. RESULTS: Using a high-content screening assay, we verified that sofosbuvir presented the best antiviral activity against YFV. Moreover, after an off-label treatment with sofosbuvir, the two female patients diagnosed with yellow fever infection displayed a reduction in blood viremia and an improvement in the course of the disease, which was observed in the laboratory medical parameters related to disease evolution. CONCLUSIONS:Sofosbuvir may be used as an option for treatment against YFV until other drugs are identified and approved for human use. These results offer insights into the role of nonstructural protein 5 (NS5) in YFV inhibition and suggest that nonstructural proteins may be explored as drug targets for YFV treatment.
Authors: Claudia Figueiredo-Mello; Luciana Vilas Boas Casadio; Vivian Iida Avelino-Silva; Ho Yeh-Li; Jaques Sztajnbok; Daniel Joelsons; Marilia Bordignon Antonio; João Renato Rebello Pinho; Fernanda de Mello Malta; Michele Soares Gomes-Gouvêa; Ana Paula Moreira Salles; Aline Pivetta Corá; Carlos Henrique Valente Moreira; Ana Freitas Ribeiro; Ana Catharina de Seixas Santos Nastri; Ceila Maria Sant'Ana Malaque; Ralcyon Francis Azevedo Teixeira; Luciana Marques Sansão Borges; Mario Peribañez Gonzalez; Luiz Carlos Pereira Junior; Tâmara Newman Lobato Souza; Alice Tung Wan Song; Luiz Augusto Carneiro D'Albuquerque; Edson Abdala; Wellington Andraus; Rodrigo Bronze de Martino; Liliana Ducatti; Guilherme Marques Andrade; Luiz Marcelo Sá Malbouisson; Izabel Marcilio de Souza; Flair José Carrilho; Ester Cerdeira Sabino; Anna S Levin Journal: BMJ Open Date: 2019-11-25 Impact factor: 2.692