Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

Several approaches, including incorporation of D-instead of L-amino acids, have been applied to increase the stability and hence efficacy of furin inhibitors. For example, hexa-D-arginine (D6R), one of the first furin inhibitors, exhibits good stability and prevents the cytotoxic effects of Pseudomonas exotoxin A in vitro and in vivo. 105 Similarly, topical application of nona-D-arginine (D9R) has been shown to reduce corneal damage in mice infected with Pseudomonas aeruginosa. 106 Interestingly, D9R also showed direct bactericidal activity, probably because of its polycationic nature. 107 Besides D-amino acids, incorporation of amino acid analogs such as decarboxylated arginine mimetics or 4-amidinobenzylamide (Amba) has been used to increase the stability of peptide-derived furin inhibitors. 108 Furthermore, the addition of a chloromethyl ketone (CMK) moiety to the C terminus of a polybasic cleavage motif has proven useful as it results in the alkylation of the active site of furin that irreversibly blocks its enzymatic activity. 109 Nevertheless, the cytotoxicity of CMKbased inhibitors and the instability of the CMK moiety may limit their use to topical applications such as the treatment of HPV skin infections. 110 Finally, the elucidation of the crystal structure of furin enabled the targeted modelling of nonpeptidic inhibitors such as streptamine-based compounds. Upon addition of guanidine residues, streptamine derivatives mimic the cationic furin cleavage site and inhibit its enzymatic activity in the nanomolar range in vitro. 111 Dahms and colleagues describe an interesting example of a 2,5dideoxystreptamine-derived inhibitor, where two molecules of the inhibitor form a complex with furin. 112 While the first inhibitor molecule directly interferes with the conformation of the catalytic triad, the second molecule binds to an adjacent planar peptide stretch.