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

Antiviral Res. 1995 May;27(1-2):59-69. doi: 10.1016/0166-3542(94)00080-r.

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 (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.

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology*
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / pharmacology
  • Chlorocebus aethiops
  • Dogs
  • Evaluation Studies as Topic
  • Female
  • Male
  • Measles virus / drug effects
  • Molecular Structure
  • Parainfluenza Virus 3, Human / drug effects
  • Phosphonoacetic Acid / analogs & derivatives*
  • Phosphonoacetic Acid / pharmacology
  • Rats
  • Respiratory Syncytial Viruses / drug effects*
  • Respirovirus / drug effects*
  • Sigmodontinae
  • Toxicity Tests
  • Tumor Cells, Cultured
  • Vero Cells

Substances

  • Antiviral Agents
  • Aspartic Acid
  • sparfosic acid
  • Phosphonoacetic Acid