title: Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases.
abstract: Optimization of our previously described peptidomimetic furin inhibitors was performed and yielded several analogs with a significantly improved activity. The most potent compounds containing an N-terminal 4- or 3-(guanidinomethyl)phenylacetyl residue inhibit furin with K(i) values of 16 and 8 pM, respectively. These analogs inhibit other proprotein convertases, such as PC1/3, PC4, PACE4, and PC5/6, with similar potency, whereas PC2, PC7, and trypsin-like serine proteases are poorly affected. Incubation of selected compounds with Madin-Darby canine kidney cells over a period of 96 h revealed that they exhibit great stability, making them suitable candidates for further studies in cell culture. Two of the most potent derivatives were used to inhibit the hemagglutinin cleavage and viral propagation of a highly pathogenic avian H7N1 influenza virus strain. The treatment with inhibitor 24 (4-(guanidinomethyl)phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide) resulted in significantly delayed virus propagation compared with an inhibitor-free control. The same analog was also effective in inhibiting Shiga toxin activation in HEp-2 cells. This antiviral effect, as well as the protective effect against a bacterial toxin, suggests that inhibitors of furin or furin-like proprotein convertases could represent promising lead structures for future drug development, in particular for the treatment of infectious diseases.
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, 35032 Marburg, Germany.
authors.forename: Gero L
authors.initials: GL
authors.lastname: Becker
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Lu
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.forename: Boris
authors.initials: B
authors.lastname: Strehlow
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
authors.forename: Udo
authors.initials: U
authors.lastname: Bakowsky
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Garten
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000818:Animals; D001550:Benzamidines / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003141:Communicable Diseases / Q000188:drug therapy*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D045683:Furin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008823:Micelles; D008956:Models, Chemical; D009842:Oligopeptides / Q000737:chemistry; D010447:Peptide Hydrolases / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D022621:Shiga Toxin / Q000737:chemistry
chemical_list: D001550:Benzamidines; D006388:Hemagglutinins; C000611989:MI-0701; D008823:Micelles; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D022621:Shiga Toxin; D010447:Peptide Hydrolases; D043484:Proprotein Convertases; D045683:Furin