Towards broad-spectrum antiviral drugs: inhibition of transmembrane serine proteases

Proteases are important for the pathogenesis of many viruses. These proteolytic enzymes cleave one or more amide bonds of viral proteins. This protein processing is required for viral entry and replication. The most widely utilized for this purpose are serine proteases, the majority of which are host cell transmembrane, or membrane associated serine proteases such as matriptase, TMPRSS2, TMPRSS11D, and TMPRSS13. Several host cysteine proteases like members of the Cathepsin family (e.g. Cathepsin L) are also highjacked by viruses to process viral proteins to infect their hosts. To target these proteases as antiviral drugs, many inhibitors, both competitive and covalent, have been developed but none have been advanced to clinical evaluation to date. Herein, we review these proteases, their viral protein substrates, pathogenesis, and their inhibitors.