A protein-based therapeutic for human cytomegalovirus infection

Current antiviral strategies target viral gene products. Although initially successful, their severe toxicity and susceptibility to circumvention by t he generation of drug-resistant variants limit their usefulness. By contras t, the central role of the host cell serine endoprotease furin in the prote olytic activation of numerous pathogens points to the endoprotease as a str ategic target for therapeutics. Herein, we show that the production of infe ctious human cytomegalovirus is dramatically reduced by exogenous addition of a bioengineered serpin, alpha(1)-PDX. This protein is a potent and selec tive furin inhibitor (K-i = 0.6 nM) and is 10-fold more effective than curr ently used antiherpetic agents in cell-culture models. The requirement of f urin for the processing of envelope glycoproteins from many pathogenic viru ses and for the activation of several bacterial toxins suggests that select ive inhibitors of furin have potential as broad-based anti-pathogens.