title: Castanospermine vs. its 6-O-butanoyl analog: a comparison of toxicity and antiviral activity in vitro and in vivo.
abstract: Inhibitors 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 microM for the 6-O-butanoyl analog of castanospermine, as compared to 9 microM for castanospermine. For both compounds, concentrations resulting in significant cytotoxicity were about ten times higher. Both compounds significantly decreased HIV-1 env-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.
authors.affiliation: Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: R M
authors.initials: RM
authors.lastname: Ruprecht
authors.forename: L D
authors.initials: LD
authors.lastname: Bernard
authors.forename: R
authors.initials: R
authors.lastname: Bronson
authors.forename: M A
authors.initials: MA
authors.lastname: Gama Sosa
authors.forename: S
authors.initials: S
authors.lastname: Mullaney
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015726:Giant Cells / Q000187:drug effects; D065089:Glycoside Hydrolase Inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007212:Indolizines; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010976:Platelet Count / Q000187:drug effects; D011446:Prospective Studies; D011925:Rauscher Virus / Q000187:drug effects* / Q000502:physiology; D010948:Viral Plaque Assay; D014766:Viremia / Q000188:drug therapy; D015431:Weight Loss / Q000187:drug effects; D054836:Indolizidines
chemical_list: D000470:Alkaloids; D065089:Glycoside Hydrolase Inhibitors; D007212:Indolizines; C037806:castanospermine; D054836:Indolizidines