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Antimicrobial Agents and Chemotherapy, October 1999, p. 2444-2450, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

In Vitro Antiviral Activity of AG7088, a Potent Inhibitor of Human Rhinovirus 3C Protease

A. K. Patick,* S. L. Binford, M. A. Brothers, R. L. Jackson, C. E. Ford, M. D. Diem, F. Maldonado, P. S. Dragovich, R. Zhou, T. J. Prins, S. A. Fuhrman, J. W. Meador, L. S. Zalman, D. A. Matthews, and S. T. Worland

Agouron Pharmaceuticals, Inc., San Diego, California 92121

Received 22 March 1999/Returned for modification 14 June 1999/Accepted 15 July 1999

AG7088 is a potent, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (kobs/[I]} = 1,470,000 ± 440,000 M-1 s-1 for HRV 14) that was discovered by protein structure-based drug design methodologies. In H1-HeLa and MRC-5 cell protection assays, AG7088 inhibited the replication of all HRV serotypes (48 of 48) tested with a mean 50% effective concentration (EC50) of 0.023 µM (range, 0.003 to 0.081 µM) and a mean EC90 of 0.082 µM (range, 0.018 to 0.261 µM) as well as that of related picornaviruses including coxsackieviruses A21 and B3, enterovirus 70, and echovirus 11. No significant reductions in the antiviral activity of AG7088 were observed when assays were performed in the presence of alpha 1-acid glycoprotein or mucin, proteins present in nasal secretions. The 50% cytotoxic concentration of AG7088 was >1,000 µM, yielding a therapeutic index of >12,346 to >333,333. In a single-cycle, time-of-addition assay, AG7088 demonstrated antiviral activity when added up to 6 h after infection. In contrast, a compound targeting viral attachment and/or uncoating was effective only when added at the initiation of virus infection. Direct inhibition of 3C proteolytic activity in infected cells treated with AG7088 was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of radiolabeled proteins, which showed a dose-dependent accumulation of viral precursor polyproteins and reduction of processed protein products. The broad spectrum of antiviral activity of AG7088, combined with its efficacy even when added late in the virus life cycle, highlights the advantages of 3C protease as a target and suggests that AG7088 will be a promising clinical candidate.

* Corresponding author. Mailing address: Department of Virology, Agouron Pharmaceuticals, Inc., 4245 Sorrento Valley Blvd., San Diego, CA 92121. Phone: (619) 622-3117. Fax: (619) 622-5999. E-mail: amy.patick{at}agouron.com.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2444-2450, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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