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Antimicrobial Agents and Chemotherapy, April 2006, p. 1470-1479, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1470-1479.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Sialidase Fusion Protein as a Novel Broad-Spectrum Inhibitor of Influenza Virus Infection

Michael P. Malakhov,1 Laura M. Aschenbrenner,1 Donald F. Smee,2 Miles K. Wandersee,2 Robert W. Sidwell,2 Larisa V. Gubareva,3 Vasiliy P. Mishin,3 Frederick G. Hayden,3 Do Hyong Kim,1 Alice Ing,1 Erin R. Campbell,1 Mang Yu,1 and Fang Fang1*

NexBio, Inc., 6330 Nancy Ridge Dr., Suite 105, San Diego, California 92121,1 Institute for Antiviral Research, Utah State University, Logan, Utah 84322,2 Division of Infectious Diseases and International Health, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 229083

Received 9 November 2005/ Returned for modification 13 January 2006/ Accepted 1 February 2006

Influenza is a highly infectious disease characterized by recurrent annual epidemics and unpredictable major worldwide pandemics. Rapid spread of the highly pathogenic avian H5N1 strain and escalating human infections by the virus have set off the alarm for a global pandemic. To provide an urgently needed alternative treatment modality for influenza, we have generated a recombinant fusion protein composed of a sialidase catalytic domain derived from Actinomyces viscosus fused with a cell surface-anchoring sequence. The sialidase fusion protein is to be applied topically as an inhalant to remove the influenza viral receptors, sialic acids, from the airway epithelium. We demonstrate that a sialidase fusion construct, DAS181, effectively cleaves sialic acid receptors used by both human and avian influenza viruses. The treatment provides long-lasting effect and is nontoxic to the cells. DAS181 demonstrated potent antiviral and cell protective efficacies against a panel of laboratory strains and clinical isolates of IFV A and IFV B, with virus replication inhibition 50% effective concentrations in the range of 0.04 to 0.9 nM. Mouse and ferret studies confirmed significant in vivo efficacy of the sialidase fusion in both prophylactic and treatment modes.

* Corresponding author. Mailing address: NexBio, Inc., 6330 Nancy Ridge Dr., Suite 105, San Diego, CA 92121. Phone: (858) 452-2631. Fax: (858) 452 0133. E-mail: ffang{at}nexbio.com.

Antimicrobial Agents and Chemotherapy, April 2006, p. 1470-1479, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1470-1479.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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