Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets
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DOI：
10.1128/mbio.01114-20
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发表时间：
2020-05-01
期刊：
影响因子：
6.4
通讯作者：
Choi, Young Ki
中科院分区：
文献类型：
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作者：
Park, Su-Jin;Yu, Kwang-Min;Choi, Young Ki
由于 2019 年冠状病毒 (CoV) 疾病 (COVID-19) 患者迫切需要治疗方法，在没有足够信息的情况下，许多 FDA 批准/改变用途的药物被建议作为临床抗病毒候选药物。此外，抗病毒候选药物针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的有效性和安全性存在广泛争论，这表明需要快速的临床前动物研究来确定用于人体试验的潜在抗病毒候选药物。为此，在雪貂感染模型中评估了洛匹那韦-利托那韦、硫酸羟氯喹和恩曲他滨-替诺福韦对 SARS-CoV-2 感染的抗病毒功效。虽然洛匹那韦-利托那韦、硫酸羟氯喹或恩曲他滨-替诺福韦治疗组的总体临床评分低于磷酸盐缓冲盐水（PBS）治疗的对照组，但鼻腔冲洗液、粪便标本和呼吸道组织中的病毒滴度在所有三个候选抗病毒药物治疗组和对照组之间相似。 PBS 处理的对照组。仅恩曲他滨-替诺福韦治疗组在感染后 8 天 (dpi) 的鼻洗液中显示出比 PBS 治疗对照组更低的病毒滴度。为了进一步探讨免疫抑制对病毒感染和临床结果的影响，用免疫抑制药物硫唑嘌呤治疗雪貂。与PBS处理的对照组相比，硫唑嘌呤免疫抑制的雪貂表现出更长的临床患病期、鼻甲中的病毒滴度更高、病毒清除延迟以及血清中和（SN）抗体滴度显着降低。总的来说，所有测试的抗病毒药物都略微降低了受感染雪貂的总体临床评分，但没有显着影响体内病毒滴度。尽管动物和人类之间的药物疗效可能存在差异，但这些临床前雪貂数据应该对未来 COVID-19 患者的治疗提供大量信息。 重要性 SARS-CoV-2 大流行继续在全球范围内蔓延，死亡率迅速增加，给医疗保健系统带来了越来越大的压力。尽管存在严重的公共卫生问题，但监管机构尚未批准任何有效的疫苗或治疗方法。在这项研究中，我们在高度易感的雪貂感染模型中测试了 FDA 批准的药物洛匹那韦-利托那韦、硫酸羟氯喹和恩曲他滨-替诺福韦对 SARS-CoV-2 感染的抵抗力。虽然大多数药物治疗略微减轻了临床症状，但并未降低病毒滴度，恩曲他滨-替诺福韦治疗除外，该治疗导致 8 dpi 鼻洗液中的病毒滴度降低。此外，硫唑嘌呤治疗的免疫抑制雪貂表现出病毒清除延迟和 SN 滴度低，导致感染时间延长。由于几种经 FDA 批准或重新调整用途的药物正在临床上作为抗病毒候选药物进行测试，但没有足够的信息，因此在进行人体功效试验之前，应继续进行快速临床前动物研究，以确定具有强大抗病毒潜力和高安全性的候选治疗药物。
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-tenofovirtreated 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.