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Antimicrobial Agents and Chemotherapy, October 1999, p. 2444-2450, Vol. 43, No. 10
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
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
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
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.
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