Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

Initially, most studies focused on peptides or proteins that bind to the active site of furin and inhibit substrate binding in a competitive manner. For example, a variant of the naturally occurring serine protease inhibitor a-1 antitrypsin was modified to harbour a consensus furin cleavage site. This variant, termed a-1 antitrypsin Portland (a1-PDX), inhibits furin and PCSK5 and has been shown to prevent the processing of HIV-1 Env and measles virus F in vitro. 99, 100 Similarly, peptides derived from the cleavage site of influenza A virus hemagglutinin and polyarginines compete with natural furin substrates. 101, 102 Even exogenous addition of the autoinhibitory propeptide of furin has been shown to reduce its enzymatic activity, limiting for example the activation of MMP9 in breast cancer cells. 103, 104 However, the therapeutic potential of the propeptide has never been evaluated in vivo and the inhibitory effects are most likely limited as it is known to dissociate from furin in the TGN.