Abstract
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.
Highlights
Influenza is an infectious viral infection that has serious impact on public health
Our findings suggest that inhibiting TMPRSS2 expression by G-quadruplex stabilization in TMPRSS2 promoter is a potential strategy for influenza A virus (IAV) infection therapy and novel benzoselenoxanthene derivatives own a potential as drugs against IAV infection
Based on the above electrophoretic mobility shift assay (EMSA) and circular dichroism (CD) results (Fig. 2B,C,E), we found that mutant single-stranded TMPRSS2-G (TMPRSS2-G-Mut) and double-stranded DNA (ds NDA (Mutant)) both cannot form G-qaudruplex under our experimental conditions
Summary
Influenza is an infectious viral infection that has serious impact on public health. Worldwide, annual influenza epidemics are estimated to result in about 3 to 5 million cases of severe illness, and about 290 000 to 650 000 respiratory deaths reported by the World Health Organization (WHO)[1]. The increasing frequencies of drug-resistant virus strain highlight the need for novel antiviral strategies, such as drugs focus on different viral targets or cellular factors. Virus entry is the first and essential step in IAV life cycle, blocking of entry would lead to suppression of viral infectivity and is an attractive antiviral strategy. Genetic variants with higher TMPRSS2 expression confer higher risk to severe H1N1 (pdm09) and Asian H7N9 influenza A virus[8]. We designed and synthesized a series of benzoselenoxanthene derivatives and found that these compounds can induce the formation of and stabilize the G-quadruplex structure in the guanine-rich tract, causing down-regulation of TMPRSS2 expression and resulted in a reduction of influenza A virus (A/ PR8/34) titers in vitro. Our findings suggest that inhibiting TMPRSS2 expression by G-quadruplex stabilization in TMPRSS2 promoter is a potential strategy for IAV infection therapy and novel benzoselenoxanthene derivatives own a potential as drugs against IAV infection
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