There is an urgent need to identify therapeutics for the treatment of Coronavirus diseases 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18% had an IC₅₀ below 25 μM or 10² IU/mL. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.

中文翻译：

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药物筛选筛选后鉴定为抗SARS-CoV-2诱导的细胞病变作用的强肽素

迫切需要确定2019年冠状病毒疾病（COVID-19）的治疗药物。尽管已为SARS-CoV-2感染的临床管理提供了不同的抗病毒药物，但其疗效仍在评估中。在这里，我们筛选了已获准在多种疾病中用于人类的现有药物，以比较它们在体外如何抵抗SARS-CoV-2诱导的细胞病变作用和病毒复制。在本文先前提出的抑制SARS-CoV-2感染的潜在72种抗病毒药中，只有18％的IC ₅₀低于25μM或10 ²IU / mL。这些药物包括普氏胃蛋白酶，新型组织蛋白酶抑制剂，甲磺酸奈非那韦水合物，干扰素2-α，干扰素-γ，非诺贝特，安定药（沿著名的雷姆昔韦和氯喹衍生物）。普立肽是唯一获得纳摩尔功效的临床批准药物。这些家族中的四个，包括新型组织蛋白酶抑制剂，以细胞类型特异性方式阻止病毒进入。由于最有效的抗病毒药通常会结合在不同感染步骤处理病毒的疗法，因此我们还评估了几种药物组合。尽管没有发现特定的协同作用，但抑制性组合并没有降低其抗病毒活性。因此，这些组合可以减少抗药性病毒的潜在出现。本文优先考虑的抗病毒药物可识别新型化合物及其作用方式，同时独立复制减少比例的药物活性，这些药物大部分已获准用于临床。这些药物的组合应在动物模型中进行测试，以指导快速临床试验的设计。