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Antimicrobial Agents and Chemotherapy, August 2003, p. 2518-2525, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2518-2525.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Potent Anti-Influenza Activity of Cyanovirin-N and Interactions with Viral Hemagglutinin

Barry R. O'Keefe,¹ Donald F. Smee,² Jim A. Turpin,^3, Carrie J. Saucedo,⁴ Kirk R. Gustafson,¹ Toshiyuki Mori,¹ Dennis Blakeslee,⁵ Robert Buckheit,^3, and Michael R. Boyd^6*

Molecular Targets Development Program, Center for Cancer Research,¹ Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick,⁴ Retrovirus Research Laboratory, Southern Research Institute, Frederick, Maryland 21702,³ Institute for Antiviral Research, Utah State University, Logan, Utah 84322,² Omniviral Therapeutics, LLC, Germantown, Maryland 20874,⁵ USA Cancer Research Institute, College of Medicine, University of South Alabama, Mobile, Alabama 36688⁶

Received 31 October 2002/ Returned for modification 22 January 2003/ Accepted 23 May 2003

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 [EC₅₀] = 1 µg/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 (EC₅₀ = 0.004 to 0.04 µg/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.

Present address: HowPin International Consulting, Frederick, MD 21705.

Present address: TherImmune Research Corporation, Gaithersburg, MD 20879.

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