Potent anti-influenza activity of cyanovirin-N and interactions with viral hemagglutinin.
The novel antiviral protein cyanovirin-N (CV-N) was initially discovered based on its potent activity against the human immunodeficiency virus (HIV). Subsequent studies identified the HIV envelope glycoproteins gp120 and gp41 as molecular targets of CV-N. More recently, mechanistic studies have shown that certain high-mannose oligosaccharides (oligomannose-8 and oligomannose-9) found on the HIV envelope glycoproteins comprise the specific sites to which CV-N binds. Such selective, carbohydrate-dependent interactions may account, at least in part, for the unusual and unexpected spectrum of antiviral activity of CV-N described herein. We screened CV-N against a broad range of respiratory and enteric viruses, as well as flaviviruses and herpesviruses. CV-N was inactive against rhinoviruses, human parainfluenza virus, respiratory syncytial virus, and enteric viruses but was moderately active against some herpesvirus and hepatitis virus (bovine viral diarrhea virus) strains (50% effective concentration [EC(50)] = approximately 1 micro g/ml) while inactive against others. Remarkably, however, CV-N and related homologs showed highly potent antiviral activity against almost all strains of influenza A and B virus, including clinical isolates and a neuraminidase inhibitor-resistant strain (EC(50) = 0.004 to 0.04 micro g/ml). When influenza virus particles were pretreated with CV-N, viral titers were lowered significantly (>1,000-fold). Further studies identified influenza virus hemagglutinin as a target for CV-N, showed that antiviral activity and hemagglutinin binding were correlated, and indicated that CV-N's interactions with hemagglutinin involved oligosaccharides. These results further reveal new potential avenues for antiviral therapeutics and prophylaxis targeting specific oligosaccharide-comprised sites on certain enveloped viruses, including HIV, influenza virus, and possibly others.
O'Keefe
Barry R
BR
Molecular Targets Development Program, Center for Cancer Research, Frederick, Maryland 21702, USA.
Smee
Donald F
DF
Turpin
Jim A
JA
Saucedo
Carrie J
CJ
Gustafson
Kirk R
KR
Mori
Toshiyuki
T
Blakeslee
Dennis
D
Buckheit
Robert
R
Boyd
Michael R
MR
D000998:Antiviral Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D001681:Biological Assay; D015153:Blotting, Western; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral; D024882:Drug Resistance, Viral; D006388:Hemagglutinins / Q000494:pharmacology*; D006801:Humans; D009975:Orthomyxoviridae / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D001426:Bacterial Proteins; D002352:Carrier Proteins; D006388:Hemagglutinins; C107733:cyanovirin N