title: Novel Furin Inhibitors with Potent Anti-infectious Activity.
abstract: New peptidomimetic furin inhibitors with unnatural amino acid residues in the P3 position were synthesized. The most potent compound 4-guanidinomethyl-phenylacteyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) inhibits furin with a Ki value of 5.5 pM. The derivatives also strongly inhibit PC1/3, whereas PC2 is less affected. Selected inhibitors were tested in cell culture for antibacterial and antiviral activity against infectious agents known to be dependent on furin activity. A significant protective effect against anthrax and diphtheria toxin was observed in the presence of the furin inhibitors. Furthermore, the spread of the highly pathogenic H5N1 and H7N1 avian influenza viruses and propagation of canine distemper virus was strongly inhibited. Inhibitor MI-1148 was crystallized in complex with human furin. Its N-terminal guanidinomethyl group in the para position of the P5 phenyl ring occupies the same position as that found previously for a structurally related inhibitor containing this substitution in the meta position, thereby maintaining all of the important P5 interactions. Our results confirm that the inhibition of furin is a promising strategy for a short-term treatment of acute infectious diseases.
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg (Germany).
authors.forename: Kornelia
authors.initials: K
authors.lastname: Hardes
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg (Germany).
authors.forename: Gero L
authors.initials: GL
authors.lastname: Becker
authors.affiliation: Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, Marburg (Germany).
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Protein Crystallography Group, Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena (Germany).
authors.forename: Sven O
authors.initials: SO
authors.lastname: Dahms
authors.affiliation: Institute of Environmental and Animal Hygiene, University of Hohenheim, Garbenstrasse 30, 70599 Stuttgart (Germany).
authors.forename: Susanne
authors.initials: S
authors.lastname: Köhler
authors.affiliation: Institute of Environmental and Animal Hygiene, University of Hohenheim, Garbenstrasse 30, 70599 Stuttgart (Germany).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Beyer
authors.affiliation: Department of Biochemistry and Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310 Oslo (Norway).
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland 21201 (USA).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland 21201 (USA).
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
authors.affiliation: Veterinary Medicine Division, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Strasse 51-59, 63225 Langen (Germany).
authors.forename: Lisa
authors.initials: L
authors.lastname: Walz
authors.affiliation: Veterinary Medicine Division, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Strasse 51-59, 63225 Langen (Germany).
authors.forename: Veronika
authors.initials: V
authors.lastname: von Messling
authors.affiliation: Protein Crystallography Group, Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena (Germany).
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Than
authors.affiliation: Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, Marburg (Germany).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Garten
authors.affiliation: Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg (Germany). steinmetzer@uni-marburg.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D004217:Distemper Virus, Canine / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C468731:FURIN protein, human; D045683:Furin
keywords: antiviral agents; crystal structure analysis; furin; inhibitors; proprotein convertases