The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti–SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective in a challenge study using hamsters as disease model.

截至 2020 年 11 月，由 SARS-CoV-2 引起的 COVID-19 疫情已导致全球确诊病例超过 5000 万例，死亡人数超过 100 万人。目前，美国食品和药物管理局还没有批准有效的抗病毒药物来遏制这种情况除了抗病毒药物瑞德西韦之外，其他大流行病都没有发生过。此外，病毒表面的三聚体刺突蛋白高度糖基化，其1,273个氨基酸序列中的1,000多个位置上有近20万个变异体，这对抗体和疫苗的开发提出了重大挑战。因此，迫切需要对该疾病进行替代且及时的治疗。在这项研究中，我们使用基于细胞的感染测定法筛选了3,000多种用于人类和动物的药物，包括2,855种小分子和190种传统草药，并鉴定了15种活性小分子，浓度范围为0.1 nM至50 μM。随后开发了两种酶测定法以及分子模型，以确认针对病毒 3CL 蛋白酶和 RNA 依赖性 RNA 聚合酶的酶测定法。几种草药的水提取物在细胞检测中具有活性，可以进一步开发为植物源性抗 SARS-CoV-2 药物。对筛选中鉴定出的一些活性化合物进行了进一步的体内测试，发现甲氟喹、奈非那韦以及灵芝（RF3）、紫苏和薄荷提取物在使用仓鼠作为疾病模型的挑战研究中是有效的。