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Castanospermine vs. Its 6‐O‐Butanoyl AnalogA Comparison of Toxicity and Antiviral Activity In Vitro and In Vivo

 

作者: Ruth Ruprecht,   Lisa Bernard,   Roderick Bronson,   Miguel Gama Sosa,   Steve Mullaney,  

 

期刊: Journal of Acquired Immune Deficiency Syndromes  (OVID Available online 1991)
卷期: Volume 4, issue 1  

页码: 48-55

 

ISSN:0894-9255

 

年代: 1991

 

出版商: OVID

 

关键词: Castanospermine;6-O-butanoylcastanospermine;Inhibition of glycosylation;Inhibition of HIV-1env-induced syncytium formation;Analysis in cultured cells and in mice;Rauscher murine leukemia virus;Toxicity;Antiviral activity

 

数据来源: OVID

 

摘要:

SummaryInhibitors of glycoprotein processing, such as castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine), have been shown previously to inhibit human immunodeficiency virus type 1 (HIV-1) with acceptable toxicity in cultured human cells. In prior experiments, we have tested the toxicity and antiviral efficacy of castanospermine in mice infected with the Rauscher murine leukemia virus (RLV). When compared with 3‘-azido-3’-deoxythymidine (AZT, zidovudine), castanospermine was less effective and more toxic. Since the 6-O-butanoyl analog of castanospermine was previously found to have a more favorable activity profile than the parent compound against HIV-1 in cultured cells, we compared the antiviral efficacy of both compounds in parallel in vitro and in vivo in the RLV system. Plaque formation in the XC assay was inhibited with a 50% inhibitory concentration (IC50) of 2.4 μMfor the 6-O-butanoyl analog of castanospermine, as compared to 9 μM for castanospermine. For both compounds, concentrations resulting in significant cytotoxicity were about ten times higher. Both compounds significantly decreased HIV-1env-induced syncytium formation in a novel in vitro assay. In RLV-exposed mice, the 6-O-butanoyl analog showed no advantage over the parent compound: both curves for toxicity as well as antiviral efficacy were super-imposable. We conclude that the 6-O-butanoyl analog of castanospermine as well as castanospermine itself are active antiviral agents in mice and that prolonged oral administration is tolerable. However, in comparison to AZT, their antiviral activity profiles are less favorable.

 

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