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

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• 作者：Wyde ; Philip R. ; Moore ; Donna K. ; Pimentel ; D. Miles ; Blough ; Herbert A.
• 关键词：Paramyxoviruses ; Respiratory syncytial virus ; Pneumonia ; Antiviral action ; N-(phosphonyl)-l-aspartate (PALA)
• 刊名：Antiviral Research
• 出版年：1995
• 出版时间：May, 1995
• 年：1995
• 卷：27
• 期：1-2
• 页码：59-69
• 全文大小：660 K

文摘

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 μg/ml) and Vero cells (IC₅₀ = 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 IC₅₀ 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 log₁₀/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.