Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics

Longlong Si; Haiqing Bai; Melissa Rodas; Wuji Cao; Crystal Yur Oh; Amanda Jiang; Atiq Nurani; Danni Y Zhu; Girija Goyal; Sarah Gilpin; Rachelle Prantil-Baun; Donald E. Ingber

Given that host serine proteases on human airway epithelial cells play critical roles in influenza virus propagation 11,18 , and their expression is significantly elevated in the differentiated Airway Chip (Fig. 1C,F) , we explored whether existing approved drugs that inhibit serine proteases could suppress infection by delivering them into the airway channel of influenza-infected chips (i.e., to mimic intratracheal delivery by aerosol, nebulizer or lavage). These studies revealed that two clinically used anticoagulant drugs, nafamostat (Fig. 3E) and trasylol (Fig. S4A) , significantly reduced influenza H1N1 and H3N2 titers on-chip. Further exploration of nafamostat's actions revealed that it protects airway barrier function (Fig. S4B ) and tight junction integrity (Fig. S4C) , and decreases production of cytokines and chemokines (Fig. S4D) . Nafamostat and the other protease inhibitor appeared to act by efficiently blocking the serine proteasemediated enzymatic cleavage of influenza viral HA0 protein into HA1 and HA2 subunits by TMPRSS11D or TMPRSS2 (Fig. S4E) .