Session: Respiratory Viral Infections
Location:
Exhibit Hall
Session Date:
Sunday, 9/26/99
Session Time:
11:00 am - 12:30 pm
Comparative In Vitro Antirhinoviral Activity of AG7088 and Pleconaril
L. Kaiser1, C. Crump1, A.K. Patick2, L.S. Zalman2, F.G. Hayden1
1Univ. of Virginia Sch. of Med.: Charlottesville, VA; 2Agouron Pharmaceuticals,
Inc.: San Diego, CA
Background: The 3C protease inhibitor AG7088 and the capsid-binding inhibitor
pleconaril are anti-picornaviral agents in clinical development. Our aim was to evaluate
the in vitro activity of these two drugs against both laboratory and primary human
rhinovirus (HRV) isolates. Methods: The 50% effective concentrations (EC50) of
AG7088 and pleconaril were determined in Ohio HeLa-I cell monolayers by a
cytopathic effect (CPE) inhibition assay read either microscopically or
spectrophotometrically after staining with 0.4% crystal violet. First passage HRV field
isolates (isolated from nasal washes from children and adults with natural colds over a 4
year time period) and 4 representative HRV serotypes (39, 16, 14 and Hanks) were
tested at three concentrations (1.0, 0.1 or 0.01 mg/ml). Results: For field isolates
(n=15), the EC50 value determined by the CPE assay ranged from <0.01 to 0.05 µg/ml
for AG7088 and from <0.01 to >1 µg/ml for pleconaril. AG7088 inhibited all field
isolates tested whereas pleconaril inhibited 13 of 15 isolates tested. The EC50 values
obtained using either microscopic or spetrophotometric methods were similar (r=0.98 for
AG7088 and r=0.99 for pleconaril). The median EC50 value for evaluable isolates (EC50
value ³ 0.01 and £ 1 µg/ml) determined microscopically was 0.018 mg/ml (0.030 µM)
(range, 0.01 to 0.05 µg/ml) for AG7088 compared to 0.082 mg/ml (0.214 µM) (range,
0.01 to 0.215 µg/ml) for pleconaril (p<0.05). Likewise, the median EC50 value
determined spectrophotometrically for evaluable isolates was 0.017 mg/ml (0.028 µM)
(range, 0.01 to 0.033 µg/ml) for AG7088 compared to 0.038 mg/ml (0.100 µM) (range,
0.014 to 0.2 µg/ml) for pleconaril (p<0.05). For 4 defined serotypes, no significant
differences in antiviral activity were observed between the drugs. The median EC50 value
determined by microscopic and spectrophotometric methods was 0.035 mg/ml (0.058
µM) (range, 0.017 to 0.05 mg/ml) and 0.02 mg/ml (0.033 µM) (range 0.02 to 0.12
mg/ml), respectively, for AG7088, compared to 0.06 mg/ml (0.157 µM) (range, 0.011 to
0.09, mg/ml) and 0.051 mg/ml (0.134 µM) (range, 0.02 to 0.12 mg/ml), respectively, for
pleconaril. Conclusions: Although under in vitro conditions AG7088 and pleconaril
have demonstrated comparable antiviral activity against 4 defined HRV serotypes, more
potent activity was demonstrated for AG7088 compared to pleconaril against HRV
clinical isolates.
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