The transmembrane serine protease inhibitors are potential antiviral drugs for 2019-nCoV targeting the insertion sequence-induced viral infectivity enhancement

In December 2019, 2019 novel coronavirus (2019-nCoV) induced an ongoing outbreak of pneumonia in Wuhan, Hubei, China. It enters into host cell via cellular receptor recognization and membrane fusion. The former is based on angiotensin converting enzyme II (ACE2). In the latter process, type II transmembrane serine proteases (TTSPs) play important roles in spike protein cleavage and activation. In this study, we used the single-cell transcriptomes of normal human lung and gastroenteric system to identify the ACE2- and TTSP-coexpressing cell composition and proportion. The results revealed that TMPRSS2 was highly co-expressed with ACE2 in the absorptive enterocytes, upper epithelial cells of esophagus and lung AT2 cells, implying the important role of TMPRSS2 in 2019-nCoV infection. Additionally, sequence and structural alignment showed that 675-QTQTNSPRRARSVAS-679 was the key sequence mediating 2019-nCoV spike protein, and there was a inserted sequence (680-SPRR-683). We speculated that this insertion sequence especially the exposed structure at R682 and R683 may enhance the recognition and cleavage activity of TMPRSS2 and then increase its viral infectivity. In conclusion, this study provides the bioinformatics and structure evidence for the increased viral infectivity of 2019-nCoV and indicates transmembrane serine protease inhibitors as the antiviral treatment options for 2019-nCoV infection targeting TMPRSS2.