Sofosbuvir inhibits yellow fever virus in vitro and in patients with acute liver failure.

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.

• Authors: Érica Araújo Mendes, Denise Regina Bairros de Pilger, Ana Catharina de Seixas Santos Nastri, Fernanda de Mello Malta, Bruno Dos Santos Pascoalino, Luiz Augusto Carneiro D'Albuquerque, Andrea Balan, Lucio Holanda Gondim de Freitas Jr, Edison Luis Durigon, Flair José Carrilho, João Renato Rebello Pinho
• Journal: Annals of hepatology (Ann Hepatol) 2019 Nov - Dec Vol. 18 Issue 6 Pg. 816-824 ISSN: 1665-2681 [Print] Mexico
• PMID: 31594756 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.

Chemical References

• Antiviral Agents
• Benzimidazoles
• Carbamates
• Fluorenes
• Imidazoles
• NS5 protein, flavivirus
• Pyrrolidines
• Viral Nonstructural Proteins
• ledipasvir
• Valine
• daclatasvir
• Sofosbuvir

Topics

• Animals
• Antiviral Agents (pharmacology, therapeutic use)
• Benzimidazoles (pharmacology)
• Carbamates
• Cell Line, Tumor
• Chlorocebus aethiops
• Compassionate Use Trials
• Drug Repositioning
• Female
• Fluorenes (pharmacology)
• Humans
• Imidazoles (pharmacology)
• In Vitro Techniques
• Liver Failure, Acute (etiology)
• Pyrrolidines
• Sofosbuvir (pharmacology, therapeutic use)
• Valine (analogs & derivatives)
• Vero Cells
• Viral Load (drug effects)
• Viral Nonstructural Proteins (antagonists & inhibitors)
• Yellow Fever (complications, drug therapy)
• Yellow fever virus (drug effects)