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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2020-06-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01114-20 |
| _version_ | 1819007265174192128 |
|---|---|
| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T00:21:50Z |
| format | Article |
| id | doaj.art-838b82e09b8e44308365a93fa9f4ed29 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-21T00:21:50Z |
| publishDate | 2020-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-838b82e09b8e44308365a93fa9f4ed292022-12-21T19:22:06ZengAmerican Society for MicrobiologymBio2150-75112020-06-0111310.1128/mBio.01114-20Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in FerretsSu-Jin Park0Kwang-Min Yu1Young-Il Kim2Se-Mi Kim3Eun-Ha Kim4Seong-Gyu Kim5Eun Ji Kim6Mark Anthony B. Casel7Rare Rollon8Seung-Gyu Jang9Min-Hyeok Lee10Jae-Hyung Chang11Min-Suk Song12Hye Won Jeong13Younho Choi14Weiqiang Chen15Woo-Jin Shin16Jae U. Jung17Young Ki Choi18Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Internal Medicine, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaDepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USADepartment of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute, Cheongju, Republic of KoreaABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.01114-20COVID-19severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)antiviral therapeuticsimmunosuppressionserum neutralizationferrets |
| spellingShingle | 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 mBio COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapeutics immunosuppression serum neutralization ferrets |
| title | 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_short | 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 |
| topic | COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapeutics immunosuppression serum neutralization ferrets |
| url | https://journals.asm.org/doi/10.1128/mBio.01114-20 |
| work_keys_str_mv | AT sujinpark antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT kwangminyu antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT youngilkim antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT semikim antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT eunhakim antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT seonggyukim antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT eunjikim antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT markanthonybcasel antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT rarerollon antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT seunggyujang antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT minhyeoklee antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT jaehyungchang antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT minsuksong antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT hyewonjeong antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT younhochoi antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT weiqiangchen antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT woojinshin antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT jaeujung antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets AT youngkichoi antiviralefficaciesoffdaapproveddrugsagainstsarscov2infectioninferrets |