Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

Caroline S de Freitas; Luiza M Higa; Carolina Q Sacramento; André C Ferreira; Patrícia A Reis; Rodrigo Delvecchio; Fabio L Monteiro; Giselle Barbosa-Lima; Harrison James Westgarth; Yasmine Rangel Vieira; Mayara Mattos; Natasha Rocha; Lucas Villas Bôas Hoelz; Rennan Papaleo Paes Leme; Mônica M Bastos; Gisele Olinto L Rodrigues; Carla Elizabeth M Lopes; Celso Martins Queiroz-Junior; Cristiano X Lima; Vivian V Costa; Mauro M Teixeira; Fernando A Bozza; Patrícia T Bozza; Nubia Boechat; Amilcar Tanuri; Thiago Moreno L Souza

doi:10.1371/journal.pntd.0007072

Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

PLoS Negl Trop Dis. 2019 Jan 30;13(1):e0007072. doi: 10.1371/journal.pntd.0007072. eCollection 2019 Jan.

Authors

Caroline S de Freitas^{1

2}, Luiza M Higa³, Carolina Q Sacramento^{1

2}, André C Ferreira^{1

2}, Patrícia A Reis¹, Rodrigo Delvecchio³, Fabio L Monteiro³, Giselle Barbosa-Lima⁴, Harrison James Westgarth³, Yasmine Rangel Vieira^{2

4}, Mayara Mattos^{1

2}, Natasha Rocha^{1

2}, Lucas Villas Bôas Hoelz⁵, Rennan Papaleo Paes Leme⁵, Mônica M Bastos⁵, Gisele Olinto L Rodrigues^{6

7}, Carla Elizabeth M Lopes^{6

7}, Celso Martins Queiroz-Junior⁸, Cristiano X Lima⁹, Vivian V Costa^{6

7}, Mauro M Teixeira^{6

10}, Fernando A Bozza^{1

4}, Patrícia T Bozza¹, Nubia Boechat⁵, Amilcar Tanuri³, Thiago Moreno L Souza^{1

2

4}

Affiliations

¹ Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brazil.
² National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil.
³ Laboratório de Virologia Molecular, Instituto de Biologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.
⁴ Instituto Nacional de Infectologia (INI), Fiocruz, Rio de Janeiro, RJ, Brazil.
⁵ Instituto de Tecnologia de Fármacos (Farmanguinhos), Fiocruz, Rio de Janeiro, RJ, Brazil.
⁶ Center for Research and Development of Pharmaceuticals, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
⁷ Research Group in Arboviral Diseases, Department of Morphology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
⁸ Cardiac Lab, Department of Morphology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.
⁹ Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
¹⁰ Immunopharmacology Lab, Department of Biochemistry and Immunology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais (UFMG), Minas Gerais, Brazil.

Abstract

Yellow fever virus (YFV) is a member of the Flaviviridae family. In Brazil, yellow fever (YF) cases have increased dramatically in sylvatic areas neighboring urban zones in the last few years. Because of the high lethality rates associated with infection and absence of any antiviral treatments, it is essential to identify therapeutic options to respond to YFV outbreaks. Repurposing of clinically approved drugs represents the fastest alternative to discover antivirals for public health emergencies. Other Flaviviruses, such as Zika (ZIKV) and dengue (DENV) viruses, are susceptible to sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Our data showed that sofosbuvir docks onto YFV RNA polymerase using conserved amino acid residues for nucleotide binding. This drug inhibited the replication of both vaccine and wild-type strains of YFV on human hepatoma cells, with EC50 values around 5 μM. Sofosbuvir protected YFV-infected neonatal Swiss mice and adult type I interferon receptor knockout mice (A129-/-) from mortality and weight loss. Because of its safety profile in humans and significant antiviral effects in vitro and in mice, Sofosbuvir may represent a novel therapeutic option for the treatment of YF. Key-words: Yellow fever virus; Yellow fever, antiviral; sofosbuvir.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology*
Chlorocebus aethiops
Disease Models, Animal
Drug Resistance, Viral*
Hep G2 Cells
Humans
Mice
Mice, Knockout
RNA, Viral / blood
RNA, Viral / drug effects*
RNA, Viral / genetics
Sofosbuvir / pharmacology*
Vero Cells
Yellow Fever / blood
Yellow Fever / drug therapy*
Yellow Fever / pathology
Yellow Fever / virology
Yellow fever virus / drug effects*
Yellow fever virus / genetics

Substances

Antiviral Agents
RNA, Viral
Sofosbuvir

Grants and funding

The financial support was provided by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ - http://www.faperj.br/ - Grant Number E-26/201.573/2014) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - http://cnpq.br/ - Grant Numbers 306389/2014-2 and 425636/2016-0). TMLS received the funds. This work has received financial support from the National Institute of Science and Technology in Dengue (INCT dengue), a scheme funded by the Brazilian National Science Council (CNPq, Brazil) and Minas Gerais Foundation for Science (FAPEMIG, Brazil). Funding was also provided by National Council for Scientific and Technological Development (CNPq), Ministry of Science, Technology, Information and Communications (no. 465313/2014-0); Ministry of Education/CAPES (no. 465313/2014-0); Research Foundation of the State of Rio de Janeiro/FAPERJ (no. 465313/2014-0) and Oswaldo Cruz Foundation/FIOCRUZ to National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.