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Antimicrobial Agents and Chemotherapy, April 1998, p. 916-920, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides

Q. May Wang,* Robert B. Johnson, Louis N. Jungheim,* Jeffrey D. Cohen, and Elcira C. Villarreal

Infectious Diseases Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Received 20 June 1997/Returned for modification 3 September 1997/Accepted 30 January 1998

The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 µM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.

* Corresponding author. Mailing address for Q. May Wang: Drop code 0444, Infectious Diseases Research, LRL, Eli Lilly and Company, Indianapolis, IN 46285. Phone: (317) 277-6975. Fax: (317) 276-1743. E-mail: qmwang{at}lilly.com. Mailing address for Louis N. Jungheim: Drop code 1523, Discovery Chemistry Research, Infectious Diseases Research, LRL, Eli Lilly and Company, Indianapolis, IN 46285. Phone: (317) 276-4249. Fax: (317) 277-2035. E-mail: Jungheim_Louis_N{at}Lilly.com.

Antimicrobial Agents and Chemotherapy, April 1998, p. 916-920, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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