Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens.
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.
Shiryaev
Sergey A
SA
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Remacle
Albert G
AG
Ratnikov
Boris I
BI
Nelson
Nicholas A
NA
Savinov
Alexei Y
AY
Wei
Ge
G
Bottini
Massimo
M
Rega
Michele F
MF
Parent
Amelie
A
Desjardins
Roxane
R
Fugere
Martin
M
Day
Robert
R
Sabet
Mojgan
M
Pellecchia
Maurizio
M
Liddington
Robert C
RC
Smith
Jeffrey W
JW
Mustelin
Tomas
T
Guiney
Donald G
DG
Lebl
Michal
M
Strongin
Alex Y
AY
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000881:Anthrax / Q000378:metabolism; D001665:Binding Sites; D045683:Furin / Q000737:chemistry*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011549:Pseudomonas / Q000378:metabolism*; D013050:Spectrometry, Fluorescence / Q000379:methods
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D010455:Peptides; D045683:Furin