Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China.
Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China.
Sci Rep. 2020 May 6;10(1):7635. doi: 10.1038/s41598-020-64368-8.
Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.
流感病毒（IAV）血凝素的蛋白水解裂解对于病毒的感染力和传播至关重要。先前已经鉴定出跨膜丝氨酸蛋白酶 TMPRSS2 是一种必需的蛋白酶，它可以裂解多种亚型流感病毒的血凝素和冠状病毒的刺突蛋白。在此，我们发现人 TMPRSS2 基因启动子区域中的一个富含鸟嘌呤的序列，在钾离子存在的情况下能够形成分子内 G-四链体，对于基因转录活性非常重要，从而影响其功能。此外，我们发现 7 种新合成的苯并硒杂蒽类似物能够稳定这种 G-四链体。更重要的是，这些化合物能够下调 TMPRSS2 基因的表达，特别是内源性 TMPRSS2 蛋白水平，从而抑制体外流感 A 病毒的繁殖。我们的研究结果为通过针对 TMPRSS2 基因 G-四链体的小分子来抑制 TMPRSS2 表达，从而抑制流感 A 病毒感染提供了一种新策略，这对于开发抗流感 A 病毒的小分子药物具有重要价值，并且可能成为抗严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的潜在候选药物。
