#Sofosbuvir as a Potential Alternative to Treat the #SARS-CoV-2 Epidemic (Sci Rep., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Sci Rep. 2020 Jun 9;10(1):9294. doi: 10.1038/s41598-020-66440-9.

Sofosbuvir as a Potential Alternative to Treat the SARS-CoV-2 Epidemic

Rodrigo Jácome 1, José Alberto Campillo-Balderas 1, Samuel Ponce de León 2, Arturo Becerra 1, Antonio Lazcano 3 4

Affiliations: 1 Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico. 2 Programa Universitario de Investigación en Salud, Universidad Nacional Autónoma de México, Mexico City, Mexico. 3 Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico. alar@ciencias.unam.mx. 4 El Colegio Nacional, Mexico City, Mexico. alar@ciencias.unam.mx.

PMID: 32518317 DOI: 10.1038/s41598-020-66440-9

 

Abstract

As of today, there is no antiviral for the treatment of the SARS-CoV-2 infection, and the development of a vaccine might take several months or even years. The structural superposition of the hepatitis C virus polymerase bound to sofosbuvir, a nucleoside analog antiviral approved for hepatitis C virus infections, with the SARS-CoV polymerase shows that the residues that bind to the drug are present in the latter. Moreover, a multiple alignment of several SARS-CoV-2, SARS and MERS-related coronaviruses polymerases shows that these residues are conserved in all these viruses, opening the possibility to use sofosbuvir against these highly infectious pathogens.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Sofosbuvir.

——

#Ribavirin, #Remdesivir, #Sofosbuvir, #Galidesivir, and #Tenofovir Against #SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study (Life Sci., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Life Sci, 117592 2020 Mar 25 [Online ahead of print]

Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir Against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study

Abdo A Elfiky 1

Affiliation: 1 Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt. Electronic address: abdo@sci.cu.edu.eg.

PMID: 32222463 DOI: 10.1016/j.lfs.2020.117592

 

Abstract

Aims:

A new human coronavirus (HCoV), which has been designated SARS-CoV-2, began spreading in December 2019 in Wuhan City, China causing pneumonia called COVID-19. The spread of SARS-CoV-2 has been faster than any other coronaviruses that have succeeded in crossing the animal-human barrier. There is concern that this new virus will spread around the world as did the previous two HCoVs-Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS)-each of which caused approximately 800 deaths in the years 2002 and 2012, respectively. Thus far, 11,268 deaths have been reported from the 258,842 confirmed infections in 168 countries.

Main methods:

In this study, the RNA-dependent RNA polymerase (RdRp) of the newly emerged coronavirus is modeled, validated, and then targeted using different anti-polymerase drugs currently on the market that have been approved for use against various viruses.

Key findings:

The results suggest the effectiveness of Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir as potent drugs against SARS-CoV-2 since they tightly bind to its RdRp. In addition, the results suggest guanosine derivative (IDX-184), Setrobuvir, and YAK as top seeds for antiviral treatments with high potential to fight the SARS-CoV-2 strain specifically.

Significance:

The availability of FDA-approved anti-RdRp drugs can help treat patients and reduce the danger of the mysterious new viral infection COVID-19. The drugs mentioned above can tightly bind to the RdRp of the SARS-CoV-2 strain and thus may be used to treat the disease. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA.

Keywords: COVID-19; Drug repurposing; Molecular docking; RdRp; SARS-CoV-2; Structural bioinformatics.

Copyright © 2020. Published by Elsevier Inc.

Conflict of interest statement – Declaration of competing interest: The author declares that there is no competing interest in this work.

Keywords: SARS-CoV-2; COVID-19; Antivirals.

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#Prediction of the #SARS-CoV-2 (2019-nCoV) 3C-like #protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug #repurposing candidates (F1000Res., abstract)

[Source: F1000 Research, full page: (LINK). Abstract, edited.]

Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

[version 1; peer review: 2 approved]

Yu Wai Chen 1,2, Chin-Pang Bennu Yiu 3, Kwok-Yin Wong1,2

Author details: 1 Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hunghom, Hong Kong; 2 State Key Laboratory of Chemical Biology and Drug Discovery, Hunghom, Hong Kong; 3 Independent Researcher, La Costa, Ma On Shan, Hong Kong

This article is included in the Disease Outbreaks gateway.

 

Abstract

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CLpro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart.  With the 3CLpro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache.  The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.

Keywords: COVID-19, SARS, 2019-nCoV, 3C-like protease, drug repurpose, antiviral, coronavirus, virtual screening, molecular modelling, ledipasvir, velpatasvir, Hepatitis C virus, HCV

Keywords: SARS-CoV-2; Antivirals; Ledipasvir; Velpatasvir; Sofosbuvir.

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Anti-HCV, #Nucleotide #Inhibitors, Repurposing Against #COVID19 (Life Sci., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Life Sci, 117477 2020 Feb 28 [Online ahead of print]

Anti-HCV, Nucleotide Inhibitors, Repurposing Against COVID-19

Abdo A Elfiky 1

Affiliation: 1 Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt; College of Applied Medical Sciences, University of Al-Jouf, Saudi Arabia. Electronic address: abdo@sci.cu.edu.eg.

PMID: 32119961 DOI: 10.1016/j.lfs.2020.117477

 

Abstract

Aims:

A newly emerged Human Coronavirus (HCoV) is reported two months ago in Wuhan, China (COVID-19). Until today >2700 deaths from the 80,000 confirmed cases reported mainly in China and 40 other countries. Human to human transmission is confirmed for COVID-19 by China a month ago. Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for >8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. The current study aims to test anti-HCV drugs against COVID-19 RNA dependent RNA polymerase (RdRp).

Materials and methods:

In this study, sequence analysis, modeling, and docking are used to build a model for Wuhan COVID-19 RdRp. Additionally, the newly emerged Wuhan HCoV RdRp model is targeted by anti-polymerase drugs, including the approved drugs Sofosbuvir and Ribavirin.

Key findings:

The results suggest the effectiveness of Sofosbuvir, IDX-184, Ribavirin, and Remidisvir as potent drugs against the newly emerged HCoV disease.

Significance:

The present study presents a perfect model for COVID-19 RdRp enabling its testing in silico against anti-polymerase drugs. Besides, the study presents some drugs that previously proved its efficiency against the newly emerged viral infection.

Keywords: COVID-19; Docking; Nucleotide inhibitors; RdRp; Sofosbuvir; Structural bioinformatics; Wuhan coronavirus.

Copyright © 2020. Published by Elsevier Inc.

Conflict of interest statement. Declaration of competing interest: The author declares that there is no competing interest in this work.

Keywords: SARS-CoV-2; COVID-19; Antivirals; Ribavirin; Sofosbuvir; Remdesivir.

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#Sofosbuvir Can Inhibit the Newly Emerged #Coronavirus (2019-nCoV) in Wuhan, #China (SSRN, abstract)

[Source: SSRN, full page: (LINK). Abstract, edited.]

Sofosbuvir Can Inhibit the Newly Emerged Coronavirus (2019-nCoV) in Wuhan, China

19 Pages Posted: 28 Jan 2020

Abdo Elfiky, Cairo University – Biophysics Department; Al Jouf University – College of Applied Medical Sciences

 

Abstract

A newly emerged Human Coronavirus (HCoV) is reported last month in Wuhan, China (2019-nCoV). Until today three deaths and more than 200 confirmed cases reported in China, Thailand, and Japan. HCoVs are zoonotic viruses that transmit from animals to humans through direct contact. Six different strains of HCoV were reported, during the last century, which has a different pathogenic burden and spread potentials. The two most famous strains of HCoVs that have significant health complications are the Severe Acute Respiratory Syndrome coronavirus (SARS CoV) and the Middle East Respiratory Syndrome coronavirus (MERS CoV). Based on the World Health Organization (WHO) reports, SARS HCoV is responsible for more than 8000 cases with confirmed 774 deaths. Additionally, MERS HCoV is responsible for 858 deaths out of about 2500 reported cases. In this study, the newly emerged Wuhan HCoV is targeted by anti-polymerase drugs including the approved Sofosbuvir and Ribavirin. Sequence analysis, modeling and docking are used to build a model for Wuhan 2019-nCoV RNA dependent RNA polymerase (RdRp). The results suggest the effectiveness of Sofosbuvir, IDX-184 and Ribavirin as a potent drug against the newly emerged HCoV disease.

Funding: None.

Declaration of Interest: All the authors declare that there is no competing interest in this work.

Keywords: Wuhan coronavirus; 2019-nCoV; RdRp; docking; structural bioinformatics; Sofosbuvir; nucleotide inhibitors

Suggested Citation: Elfiky, Abdo, Sofosbuvir Can Inhibit the Newly Emerged Coronavirus (2019-nCoV) in Wuhan, China (1/20/2020). Available at SSRN: https://ssrn.com/abstract=3523869

Keywords: Antivirals; Sofosbuvir; 2019-nCoV.

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Characterization of #Usutu virus NS5 protein. #Polymerase activity, protein-protein interaction and cellular localization (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Characterization of Usutu virus NS5 protein. Polymerase activity, protein-protein interaction and cellular localization.

L. Albentosa-González, P. Clemente-Casares, R. Sabariegos, A. Mas

DOI: 10.1128/AAC.01573-19

 

ABSTRACT

Usutu virus (USUV) has become increasingly relevant in recent years with large outbreaks that sporadically have affected humans, being reported in wildlife. Similarly to the rest of flaviviruses, USUV contains a positive single-stranded RNA genome which is replicated by the activity of the non-structural protein 5 (NS5). USUV NS5 shows high sequence identity with the remaining viruses in this genus. This permitted us to identify the predicted methyl-transferase domain and the RNA-dependent RNA polymerase domain (RdRpD). Owing to their high degree of conservation, viral polymerases are considered priority targets for the development of antiviral compounds. In the present study, we have cloned and expressed the entire NS5 and the RdRpD in a heterologous system and have used purified preparations for protein characterizations. We have determined the optimal reaction conditions by investigating how variations in different physicochemical parameters, such as buffer concentration, temperature, and pH, affect RNA polymerization activity. We also found that USUV polymerase, but not the full-length NS5, exhibits cooperative activity in the synthesis of RNA, and that the RdRp activity is not inhibited by Sofosbuvir. To further examine the characteristics of USUV polymerase in a more biological context, we have expressed NS5 and the RdRpD in eukaryotic cells and analyzed its subcellular location. NS5 is predominantly found in the cytoplasm, a significant proportion is directed to the nucleus and this translocation involves nuclear location signals (NLS) located, at least, between the MTase and RdRpD domains.

Copyright © 2019 Albentosa-González et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Arbovirus; Flavivirus; Usutu virus; Viral pathogenesis.

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Characterization of #Usutu virus NS5 protein. #Polymerase activity, protein-protein interaction and cellular localization (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Characterization of Usutu virus NS5 protein. Polymerase activity, protein-protein interaction and cellular localization.

L. Albentosa-González, P. Clemente-Casares, R. Sabariegos, A. Mas

DOI: 10.1128/AAC.01573-19

 

ABSTRACT

Usutu virus (USUV) has become increasingly relevant in recent years with large outbreaks that sporadically have affected humans, being reported in wildlife. Similarly to the rest of flaviviruses, USUV contains a positive single-stranded RNA genome which is replicated by the activity of the non-structural protein 5 (NS5). USUV NS5 shows high sequence identity with the remaining viruses in this genus. This permitted us to identify the predicted methyl-transferase domain and the RNA-dependent RNA polymerase domain (RdRpD). Owing to their high degree of conservation, viral polymerases are considered priority targets for the development of antiviral compounds. In the present study, we have cloned and expressed the entire NS5 and the RdRpD in a heterologous system and have used purified preparations for protein characterizations. We have determined the optimal reaction conditions by investigating how variations in different physicochemical parameters, such as buffer concentration, temperature, and pH, affect RNA polymerization activity. We also found that USUV polymerase, but not the full-length NS5, exhibits cooperative activity in the synthesis of RNA, and that the RdRp activity is not inhibited by Sofosbuvir. To further examine the characteristics of USUV polymerase in a more biological context, we have expressed NS5 and the RdRpD in eukaryotic cells and analyzed its subcellular location. NS5 is predominantly found in the cytoplasm, a significant proportion is directed to the nucleus and this translocation involves nuclear location signals (NLS) located, at least, between the MTase and RdRpD domains.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Flavivirus; Usutu Virus; Sofosbuvir.

——

Beyond Members of the #Flaviviridae Family, #Sofosbuvir Also Inhibits #Chikungunya Virus Replication (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Beyond Members of the Flaviviridae Family, Sofosbuvir Also Inhibits Chikungunya Virus Replication

André C. Ferreira, Patrícia A. Reis, Caroline S. de Freitas, Carolina Q. Sacramento, Lucas Villas Bôas Hoelz, Mônica M. Bastos, Mayara Mattos, Natasha Rocha,Isaclaudia Gomes de Azevedo Quintanilha, Carolina da Silva Gouveia Pedrosa, Leticia Rocha Quintino Souza, Erick Correia Loiola, Pablo Trindade, Yasmine Rangel Vieira,Giselle Barbosa-Lima, Hugo C. de Castro Faria Neto, Nubia Boechat, Stevens K. Rehen, Karin Brüning, Fernando A. Bozza, Patrícia T. Bozza, Thiago Moreno L. Souza

DOI: 10.1128/AAC.01389-18

 

ABSTRACT

Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir than were hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg of body weight/day and prevented mortality in a neonate mouse model at 40- and 80-mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Alphavirus; Chikungunya fever; Antivirals; Sofosbuvir.

——

#Yellowfever virus is susceptible to #sofosbuvir both in vitro and in vivo (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Yellow fever virus is susceptible to sofosbuvir both in vitroand 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,  [ … ], Thiago Moreno L. Souza

Published: January 30, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007072 / This is an uncorrected proof.

 

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

 

Author summary

Yellow fever virus is transmitted by mosquitoes and its infection may be asymptomatic or lead to a wide clinical spectrum ranging from a mild febrile illness to a potentially lethal viral hemorrhagic fever characterized by liver damage. Although a yellow fever vaccine is available, low coverage allows 80,000–200,000 cases and 30,000–60,000 deaths annually worldwide. There are no specific therapy and treatment relies on supportive care, reinforcing an urgent need for antiviral repourposing. Here, we showed that sofosbuvir, clinically approved against hepatitis C, inhibits yellow fever virus replication in liver cell lines and animal models. In vitro, sofosbuvir inhibits viral RNA replication, decreases the number of infected cells and the production of infectious virus particles. These data is particularly relevante since the liver is the main target of yellow fever infection. Sofosbuvir also protected infected animals from mortality, weight loss and liver injury, especially prophylatically. Our pre-clinical results supports a second use of sofosbuvir against yellow fever.

___

Citation: de Freitas CS, Higa LM, Sacramento CQ, Ferreira AC, Reis PA, Delvecchio R, et al. (2019) Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo. PLoS Negl Trop Dis 13(1): e0007072. https://doi.org/10.1371/journal.pntd.0007072

Editor: Samuel V. Scarpino, Northeastern University, UNITED STATES

Received: March 25, 2018; Accepted: December 12, 2018; Published: January 30, 2019

Copyright: © 2019 de Freitas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

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.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Yellow Fever; Flavivirus; Antivirals; Sofosbuvir; Animal models.

——

Beyond members of the #Flaviviridae family, #sofosbuvir also inhibits #chikungunya virus #replication (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication

André C. Ferreira, Patrícia A. Reis, Caroline S. de Freitas, Carolina Q. Sacramento, Lucas Villas Bôas Hoelz, Mônica M. Bastos, Mayara Mattos, Natasha Rocha,Isaclaudia Gomes de Azevedo Quintanilha, Carolina da Silva Gouveia Pedrosa, Leticia Rocha Quintino Souza, Erick Correia Loiola, Pablo Trindade, Yasmine Rangel Vieira,Giselle Barbosa-Lima, Hugo C. de Castro Faria Neto, Nubia Boechat, Stevens K. Rehen, Karin Brüning, Fernando A. Bozza, Patrícia T. Bozza, Thiago Moreno L. Souza

DOI: 10.1128/AAC.01389-18

 

ABSTRACT

Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell–derived astrocytes was less susceptible to sofosbuvir compared to the hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection–dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg/day, and prevented mortality in a neonate mouse model at 40 and 80 mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Arbovirus; Alphavirus; Flavivirus; Antivirals; Sofosbuvir.

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