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Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets.
mBio. 2020 05 22; 11(3)MBIO

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.

Authors+Show Affiliations

Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.Department of Internal Medicine, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea.Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA jaeujung@med.usc.edu choiki55@chungbuk.ac.kr.Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of Korea jaeujung@med.usc.edu choiki55@chungbuk.ac.kr. Zoonotic Infectious Disease Research Center, Chungbuk National University, Cheongju, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32444382

Citation

Park, Su-Jin, et al. "Antiviral Efficacies of FDA-Approved Drugs Against SARS-CoV-2 Infection in Ferrets." MBio, vol. 11, no. 3, 2020.
Park SJ, Yu KM, Kim YI, et al. Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets. mBio. 2020;11(3).
Park, S. J., Yu, K. M., Kim, Y. I., Kim, S. M., Kim, E. H., Kim, S. G., Kim, E. J., Casel, M. A. B., Rollon, R., Jang, S. G., Lee, M. H., Chang, J. H., Song, M. S., Jeong, H. W., Choi, Y., Chen, W., Shin, W. J., Jung, J. U., & Choi, Y. K. (2020). Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets. MBio, 11(3). https://doi.org/10.1128/mBio.01114-20
Park SJ, et al. Antiviral Efficacies of FDA-Approved Drugs Against SARS-CoV-2 Infection in Ferrets. mBio. 2020 05 22;11(3) PubMed PMID: 32444382.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets. AU - Park,Su-Jin, AU - Yu,Kwang-Min, AU - Kim,Young-Il, AU - Kim,Se-Mi, AU - Kim,Eun-Ha, AU - Kim,Seong-Gyu, AU - Kim,Eun Ji, AU - Casel,Mark Anthony B, AU - Rollon,Rare, AU - Jang,Seung-Gyu, AU - Lee,Min-Hyeok, AU - Chang,Jae-Hyung, AU - Song,Min-Suk, AU - Jeong,Hye Won, AU - Choi,Younho, AU - Chen,Weiqiang, AU - Shin,Woo-Jin, AU - Jung,Jae U, AU - Choi,Young Ki, Y1 - 2020/05/22/ PY - 2020/5/24/entrez PY - 2020/5/24/pubmed PY - 2020/6/4/medline KW - COVID-19 KW - antiviral therapeutics KW - ferrets KW - immunosuppression KW - serum neutralization KW - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) JF - mBio JO - mBio VL - 11 IS - 3 N2 - 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. SN - 2150-7511 UR - https://www.unboundmedicine.com/medline/citation/32444382/Antiviral_Efficacies_of_FDA_Approved_Drugs_against_SARS_CoV_2_Infection_in_Ferrets_ L2 - http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=32444382 DB - PRIME DP - Unbound Medicine ER -