Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens.

Abstract

Pathogens or their toxins, including influenza virus, Pseudomonas, and anthrax toxins, require processing by host proprotein convertases (PCs) to enter host cells and to cause disease. Conversely, inhibiting PCs is likely to protect host cells from multiple furin-dependent, but otherwise unrelated, pathogens. To determine if this concept is correct, we designed specific nanomolar inhibitors of PCs modeled from the extended cleavage motif TPQRERRRKKR downward arrowGL of the avian influenza H5N1 hemagglutinin. We then confirmed the efficacy of the inhibitory peptides in vitro against the fluorescent peptide, anthrax protective antigen (PA83), and influenza hemagglutinin substrates and also in mice in vivo against two unrelated toxins, anthrax and Pseudomonas exotoxin. Peptides with Phe/Tyr at P1' were more selective for furin. Peptides with P1' Thr were potent against multiple PCs. Our strategy of basing the peptide sequence on a furin cleavage motif known for an avian flu virus shows the power of starting inhibitor design with a known substrate. Our results confirm that inhibiting furin-like PCs protects the host from the distinct furin-dependent infections and lay a foundation for novel, host cell-focused therapies against acute diseases.

• Authors: Sergey A Shiryaev, Albert G Remacle, Boris I Ratnikov, Nicholas A Nelson, Alexei Y Savinov, Ge Wei, Massimo Bottini, Michele F Rega, Amelie Parent, Roxane Desjardins, Martin Fugere, Robert Day, Mojgan Sabet, Maurizio Pellecchia, Robert C Liddington, Jeffrey W Smith, Tomas Mustelin, Donald G Guiney, Michal Lebl, Alex Y Strongin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 29 Pg. 20847-53 (Jul 20 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17537721 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hemagglutinin Glycoproteins, Influenza Virus
• Peptides
• Furin

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Animals
• Anthrax (metabolism)
• Binding Sites
• Furin (chemistry)
• Hemagglutinin Glycoproteins, Influenza Virus (metabolism)
• Mice
• Mice, Inbred C57BL
• Models, Chemical
• Molecular Sequence Data
• Peptides (chemistry)
• Protein Binding
• Pseudomonas (metabolism)
• Spectrometry, Fluorescence (methods)