2. Academic Validation
  3. Novel Furin Inhibitors with Potent Anti-infectious Activity

Novel Furin Inhibitors with Potent Anti-infectious Activity

  • ChemMedChem. 2015 Jul;10(7):1218-31. doi: 10.1002/cmdc.201500103.
Kornelia Hardes 1,  Gero L Becker 1,  Yinghui Lu 2,  Sven O Dahms 3,  Susanne Köhler 4,  Wolfgang Beyer 4,  Kirsten Sandvig 5,  Hiroyuki Yamamoto 6,  Iris Lindberg 6,  Lisa Walz 7,  Veronika von Messling 7,  Manuel E Than 3,  Wolfgang Garten 2,  Torsten Steinmetzer 8
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg (Germany).
  • 2 Institute of Virology, Philipps University, Hans-Meerwein-Strasse 2, Marburg (Germany).
  • 3 Protein Crystallography Group, Leibniz Institute for Age Research-Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena (Germany).
  • 4 Institute of Environmental and Animal Hygiene, University of Hohenheim, Garbenstrasse 30, 70599 Stuttgart (Germany).
  • 5 Department of Biochemistry and Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310 Oslo (Norway).
  • 6 Department of Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland 21201 (USA).
  • 7 Veterinary Medicine Division, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Strasse 51-59, 63225 Langen (Germany).
  • 8 Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg (Germany). [email protected].
PMID: 25974265 DOI: 10.1002/cmdc.201500103
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.

Keywords

antiviral agents; crystal structure analysis; furin; inhibitors; proprotein convertases.

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