Figure 1
Hit compound ABMA identified as an inhibitor of ricin by HTS. (A) Chemical structure of ABMA. (B) Intoxication of pulmonary A549 cells by increasing concentrations of ricin in the presence of 3, 10 and 30 µM of ABMA. A549 cells were incubated 4 h in DMEM with ABMA (open and half-filled circles), or solvent only as control (DMSO, black circles) before addition of increasing concentrations of ricin for 20 h. Media was removed and replaced with DMEM containing [14C]-leucine at 0.5 µCi/mL for 6 h. Protein synthesis was measured by scintillation counting as the amount of [14C]-leucine incorporated in cells. Each data point represents the mean of duplicate ± SD of a representative experiment. (C) ABMA protects mice against ricin challenge. The survival of mice treated once with the indicated doses of ABMA and then exposed to an LD90 of ricin via nasal instillation was monitored. In each experiment, treated animals received a single ip dose of ABMA (2 mg/kg, open circles; 20 mg/kg, circles with right half black; and 200 mg/kg, circles with left half black) 1 h prior to toxin exposure (2 µg/kg by nasal instillation), while control animals (black circles) received vehicle only prior to ricin administration. The curves for treated animals are statistically different from control as measured by the log rank test (p < 0.01 for 2 mg/kg of ABMA; p < 0.001 for 20 mg/kg,; p < 0.001 for 200 mg/kg).
