College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Shandong Provincial Collaborative Innovation Center for Antiviral Traditional Chinese Medicine, Jinan 250355, China.
Viruses. 2019 Sep 5;11(9):826. doi: 10.3390/v11090826.
Influenza A virus infections cause significant morbidity and mortality, and novel antivirals are urgently needed. Influenza RNA-dependent RNA polymerase (RdRp) activity has been acknowledged as a promising target for novel antivirals. In this study, a phenotypic versus target-based screening strategy was established to identify the influenza A virus inhibitors targeting the virus RNA transcription/replication steps by sequentially using an RdRp-targeted screen and a replication-competent reporter virus-based approach using the same compounds. To demonstrate the utility of this approach, a pilot screen of a library of 891 compounds derived from natural products was carried out. Quality control analysis indicates that the primary screen was robust for identification of influenza A virus inhibitors targeting RdRp activity. Finally, two hit candidates were identified, and one was validated as a putative RdRp inhibitor. This strategy can greatly reduce the number of false positives and improve the accuracy and efficacy of primary screening, thereby providing a powerful tool for antiviral discovery.
甲型流感病毒感染会导致严重的发病率和死亡率，因此迫切需要新型抗病毒药物。流感 RNA 依赖性 RNA 聚合酶（RdRp）活性已被认为是新型抗病毒药物的一个有前途的靶点。在这项研究中，通过依次使用 RdRp 靶向筛选和使用相同化合物的复制型报告病毒方法，建立了一种基于表型与基于靶标的筛选策略，以鉴定针对病毒 RNA 转录/复制步骤的甲型流感病毒抑制剂。为了证明该方法的实用性，对来自天然产物的 891 种化合物文库进行了初步筛选。质量控制分析表明，针对 RdRp 活性的流感病毒抑制剂的初步筛选具有稳健性。最后，鉴定出两个命中候选物，其中一个被验证为潜在的 RdRp 抑制剂。该策略可以大大减少假阳性的数量，提高初步筛选的准确性和效果，从而为抗病毒药物发现提供了有力工具。
