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

Abstract

Abstract The 2019 novel coronavirus (2019-nCoV) induces an ongoing outbreak of pneumonia in China. The rapidly increasing infected cases suggest its effective transmission among humans, which largely depends on virus-binding host cell receptors and host cell proteases-cleaving virus spike protein. In order to identify the virus transmission of 2019-nCoV, the protease-induced spike protein cleavage ability between 2019-nCoV and SARS-CoV were compared. By protein sequence aligment and structure comparison, we found the key sequence of 675-QTQTNSPRRARSVAS-679 mediating 2019-nCoV spike protein cleavage. Its furin score (0.688) was higher than that of the corresponding sequence in SARS-CoV (0.139). In addition, the fragment of 680-SPRR-683 added two arginine hydrolysis sites (R682 and R683) on the surface and formed a loop for protease recognition. The molecular docking was based on the transmembrane serine protease (TMPRSS), the main proteases in coronavirus cleavage. Furthermore, as the cell receptor angiotensin converting enzyme II (ACE2) and cell proteases TMPRSSs are located in the same cell, the single-cell transcriptomes of normal human lung and gastroenteric system were used. The ACE2 and TMPRSSs were highly co-expressed in absorptive enterocytes, upper epithelial cells of esophagus and lung AT2 cells. In conclusion, this study provides the bioinformatics evidence for the increased viral infectivity of 2019-nCoV and indicates alveolus pulmonis, intestinal epithelium and esophagus epithelium as the potential target tissues. Due to the important roles of TMPRSSs in 2019-nCoV infection, transmembrane serine protease inhibitors may be the potential antiviral treatment options for 2019-nCoV infection.