Evaluation of the antiviral activity of N-(phosphonoacetyl)- l-aspartate against paramyxoviruses in tissue culture and against respiratory syncytial virus in cotton rats

Abstract

N-(phosphonoacetyl)- l-aspartate (PALA), a potent inhibitor of l-aspartic acid transcarbamoylase, was evaluated for cytotoxicity and antiviral activity against three different paramyxoviruses in tissue culture, and for antiviral efficacy and toxicity in vivo using a cotton rat-respiratory syncytial virus (RSV) model. Significant in vitro cytotoxicity was observed in proliferating cultures of HEp-2 (IC 50 = 250 μg/ml) and Vero cells (IC 50 = 32 μg/ml), but was less evident in cultures containing confluent monolayers (i.e., stationary cells) of these cells, or in cultures of Madin Darby canine kidney (MDCK) cells (these IC0 50 values were all ≥ 750 μg/ml, with 1000 μg/ml being the maximum concentration tested). Mean selective indices (ratio of the median cytotoxic dose : median efficacious dose) of 1, 72 and 146 were obtained against parainfluenza virus type 3, RSV and measles virus, respectively, when PALA was tested against these viruses using confluent HEp-2 and Vero cell monolayers. In cotton rats, significant reductions in pulmonary titers (0.8–1.4 log 10/g lung) compared to pulmonary viral titers in placebo-treated control animals, were consistently seen in cotton rats given ≥10 mg of PALA/kg/day (b.i.d.) intraperitoneally on days 1–3 postinfection with either subtype A or B RSV. No toxic effects were noted even in animals given 100 mg of PALA/kg/day for 7 consecutive days.