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Antimicrobial Agents and Chemotherapy, March 1998, p. 640-646, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection

Dirk B. Mendel,1,* Chun Y. Tai,1 Paul A. Escarpe,1 Weixing Li,1 Robert W. Sidwell,2 John H. Huffman,2 Clive Sweet,3 Kenneth J. Jakeman,3 James Merson,4 Steven A. Lacy,1 Willard Lew,1 Matthew A. Williams,1 Lijun Zhang,1 Ming S. Chen,1 Norbert Bischofberger,1 and Choung U. Kim1,*

Gilead Sciences, Inc., Foster City, California 944041; Institute for Antiviral Research, Utah State University, Logan, Utah 84322-56002; and School of Biological Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT,3 and Pfizer Central Research, Sandwich, Kent CT139 NJ,4 United Kingdom

Received 11 August 1997/Returned for modification 9 October 1997/Accepted 22 December 1997

We have recently described GS 4071, a carbocyclic transition-state analog inhibitor of the influenza virus neuraminidase, which has potent inhibitory activity comparable to that of 4-guanidino-Neu5Ac2en (GG167; zanamivir) when tested against influenza A virus replication and neuraminidase activity in vitro. We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg/kg/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.

* Corresponding author. Mailing address: D. B. Mendel, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 573-4839. Fax: (650) 573-4890. E-mail: dirk_mendel{at}gilead.com. C. U. Kim, Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404. Phone: (650) 572-6616. Fax: (650) 573-4899. E-mail: choung-kim{at}gilead.com.

Antimicrobial Agents and Chemotherapy, March 1998, p. 640-646, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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