Evaluation of the antiviral activity of N-(phosphonoacetyl)-L-aspartate against paramyxoviruses in tissue culture and against respiratory syncytial virus in cotton rats.
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 (IC50 = 250 micrograms/ml) and Vero cells (IC50 = 32 micrograms/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 IC50 values were all > or = 750 micrograms/ml, with 1000 micrograms/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 log10/g lung) compared to pulmonary viral titers in placebo-treated control animals, were consistently seen in cotton rats given > or = 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.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004285:Dogs; D005069:Evaluation Studies as Topic; D005260:Female; D008297:Male; D008459:Measles virus / Q000187:drug effects; D015394:Molecular Structure; D010224:Parainfluenza Virus 3, Human / Q000187:drug effects; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D018108:Respirovirus / Q000187:drug effects*; D016205:Sigmodontinae; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured; D014709:Vero Cells
D000998:Antiviral Agents; D001224:Aspartic Acid; C013195:sparfosic acid; D010746:Phosphonoacetic Acid