Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets

ABSTRACT Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over ant...

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Autores principales:	Su-Jin Park, Kwang-Min Yu, Young-Il Kim, Se-Mi Kim, Eun-Ha Kim, Seong-Gyu Kim, Eun Ji Kim, Mark Anthony B. Casel, Rare Rollon, Seung-Gyu Jang, Min-Hyeok Lee, Jae-Hyung Chang, Min-Suk Song, Hye Won Jeong, Younho Choi, Weiqiang Chen, Woo-Jin Shin, Jae U. Jung, Young Ki Choi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapeutics immunosuppression serum neutralization ferrets Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/838b82e09b8e44308365a93fa9f4ed29
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spelling	oai:doaj.org-article:838b82e09b8e44308365a93fa9f4ed292021-11-15T15:56:47ZAntiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets10.1128/mBio.01114-202150-7511https://doaj.org/article/838b82e09b8e44308365a93fa9f4ed292020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01114-20https://doaj.org/toc/2150-7511ABSTRACT Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients. IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.Su-Jin ParkKwang-Min YuYoung-Il KimSe-Mi KimEun-Ha KimSeong-Gyu KimEun Ji KimMark Anthony B. CaselRare RollonSeung-Gyu JangMin-Hyeok LeeJae-Hyung ChangMin-Suk SongHye Won JeongYounho ChoiWeiqiang ChenWoo-Jin ShinJae U. JungYoung Ki ChoiAmerican Society for MicrobiologyarticleCOVID-19severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)antiviral therapeuticsimmunosuppressionserum neutralizationferretsMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapeutics immunosuppression serum neutralization ferrets Microbiology QR1-502
spellingShingle	COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapeutics immunosuppression serum neutralization ferrets Microbiology QR1-502 Su-Jin Park Kwang-Min Yu Young-Il Kim Se-Mi Kim Eun-Ha Kim Seong-Gyu Kim Eun Ji Kim Mark Anthony B. Casel Rare Rollon Seung-Gyu Jang Min-Hyeok Lee Jae-Hyung Chang Min-Suk Song Hye Won Jeong Younho Choi Weiqiang Chen Woo-Jin Shin Jae U. Jung Young Ki Choi Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
description	ABSTRACT Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients. IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.
format	article
author	Su-Jin Park Kwang-Min Yu Young-Il Kim Se-Mi Kim Eun-Ha Kim Seong-Gyu Kim Eun Ji Kim Mark Anthony B. Casel Rare Rollon Seung-Gyu Jang Min-Hyeok Lee Jae-Hyung Chang Min-Suk Song Hye Won Jeong Younho Choi Weiqiang Chen Woo-Jin Shin Jae U. Jung Young Ki Choi
author_facet	Su-Jin Park Kwang-Min Yu Young-Il Kim Se-Mi Kim Eun-Ha Kim Seong-Gyu Kim Eun Ji Kim Mark Anthony B. Casel Rare Rollon Seung-Gyu Jang Min-Hyeok Lee Jae-Hyung Chang Min-Suk Song Hye Won Jeong Younho Choi Weiqiang Chen Woo-Jin Shin Jae U. Jung Young Ki Choi
author_sort	Su-Jin Park
title	Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
title_short	Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
title_full	Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
title_fullStr	Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
title_full_unstemmed	Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
title_sort	antiviral efficacies of fda-approved drugs against sars-cov-2 infection in ferrets
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/838b82e09b8e44308365a93fa9f4ed29
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Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets

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