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

Author(s):Show less -

Mendes, Erica Araujo ^[1] ; Bairros de Pilger, Denise Regina ^{[1, 2]} ; de Seixas Santos Nastri, Ana Catharina ^{[3, 4]} ; Malta, Fernanda de Mello ^[3] ; Pascoalino, Bruno dos Santos ^[1] ; Carneiro D'Albuquerque, Luiz Augusto ^[3] ; Balan, Andrea ^[1] ; Gondim de Freitas Jr, Lucio Holanda ; Durigon, Edison Luis ^[5] ; Carrilho, Flair Jose ^[3] ; Rebello Pinho, Joao Renato ^{[6, 7, 3]}

Affiliation

^[1] Univ Sao Paulo, Biomed Sci Inst, Dept Microbiol, Sao Paulo, SP - Brazil

^[2] Butantan Inst, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Sch Med, Inst Trop Med, Dept Gastroenterol, LIM 07, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Sch Med, Dept Parasit & Infect Dis, Sao Paulo, SP - Brazil

^[5] Gondim de Freitas Jr, Jr., Lucio Holanda, Univ Sao Paulo, Biomed Sci Inst, Dept Microbiol, Sao Paulo, SP - Brazil

^[6] Hosp Israelita Albert Einstein, Sao Paulo, SP - Brazil

^[7] Univ Sao Paulo, Sao Paulo Sch Med, Clin Hosp, Cent Labs Div, LIM 03, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: ANNALS OF HEPATOLOGY; v. 18, n. 6, p. 816-824, NOV-DEC 2019.
• Web of Science Citations: 0

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. (C) 2019 Fundacion Clinica Medica Sur, A.C. Published by Elsevier Espana, S.L.U. (AU)

• FAPESP's process: 16/20045-7 - Antigen discovery and development of serological diagnostic methods and vaccine approaches against the Zika Virus (ZIKV)
• Grantee: Luis Carlos de Souza Ferreira
• Support Opportunities: Research Projects - Thematic Grants