title: A protein-based therapeutic for human cytomegalovirus infection.
abstract: Current antiviral strategies target viral gene products. Although initially successful, their severe toxicity and susceptibility to circumvention by the generation of drug-resistant variants limit their usefulness. By contrast, the central role of the host cell serine endoprotease furin in the proteolytic activation of numerous pathogens points to the endoprotease as a strategic target for therapeutics. Herein, we show that the production of infectious human cytomegalovirus is dramatically reduced by exogenous addition of a bioengineered serpin, alpha(1)-PDX. This protein is a potent and selective furin inhibitor (K(i) = 0.6 nM) and is 10-fold more effective than currently used antiherpetic agents in cell-culture models. The requirement of furin for the processing of envelope glycoproteins from many pathogenic viruses and for the activation of several bacterial toxins suggests that selective inhibitors of furin have potential as broad-based anti-pathogens.
authors.affiliation: Vollum Institute, and Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97201, USA.
authors.forename: F
authors.initials: F
authors.lastname: Jean
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.forename: S S
authors.initials: SS
authors.lastname: Molloy
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: M A
authors.initials: MA
authors.lastname: Jarvis
authors.forename: J A
authors.initials: JA
authors.lastname: Nelson
authors.forename: G
authors.initials: G
authors.lastname: Thomas
mesh_terms: D015153:Blotting, Western; D003587:Cytomegalovirus / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D045683:Furin; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D011233:Precipitin Tests; D013381:Subtilisins / Q000037:antagonists & inhibitors; D013997:Time Factors; D014407:Tumor Cells, Cultured; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D000515:alpha 1-Antitrypsin; C113421:alpha 1-antitrypsin Portland; D013381:Subtilisins; D045683:Furin