Viruses possessing class I fusion proteins require proteolytic activation by host cell proteases to mediate fusion with the host cell membrane. The mammalian SPINT2 gene encodes a protease inhibitor that targets trypsin-like serine proteases. Here we show the protease inhibitor, SPINT2, restricts cleavage-activation efficiently for a range of influenza viruses and for human metapneumovirus (HMPV). SPINT2 treatment resulted in the cleavage and fusion inhibition of full-length influenza A/CA/04/09 (H1N1) HA, A/Aichi/68 (H3N2) HA, A/Shanghai/2/2013 (H7N9) HA and HMPV F when activated by trypsin, recombinant matriptase or KLK5. We also demonstrate that SPINT2 was able to reduce viral growth of influenza A/CA/04/09 H1N1 and A/X31 H3N2 in cell culture by inhibiting matriptase or TMPRSS2. Moreover, inhibition efficacy did not differ whether SPINT2 was added at the time of infection or 24 h post-infection. Our data suggest that the SPINT2 inhibitor has a strong potential to serve as a novel broad-spectrum antiviral.

中文翻译：

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SPINT2抑制涉及流感病毒和间质肺病毒激活的蛋白酶。

拥有I类融合蛋白的病毒需要宿主细胞蛋白酶进行蛋白水解激活，以介导与宿主细胞膜的融合。哺乳动物SPINT2基因编码靶向胰蛋白酶样丝氨酸蛋白酶的蛋白酶抑制剂。在这里，我们显示蛋白酶抑制剂SPINT2有效限制了一系列流感病毒和人间质肺病毒（HMPV）的裂解激活。SPINT2处理导致全长流感A / CA / 04/09（H1N1）HA，A / Aichi / 68（H3N2）HA，A / Shanghai / 2/2013（H7N9）HA和HMPV F的切割和融合抑制当被胰蛋白酶，重组matriptase或KLK5激活时。我们还证明，SPINT2能够通过抑制脱氧核糖核酸酶或TMPRSS2减少细胞培养中A / CA / 04/09 H1N1和A / X31 H3N2流感病毒的生长。此外，是否在感染时或感染后24小时添加SPINT2，抑制效果没有差异。我们的数据表明SPINT2抑制剂具有作为新型广谱抗病毒药的强大潜力。