Oral treatment of mice, cutaneously infected with herpes simplex virus type 1 (HSV-1) (strain SC16), with the alpha-glucosidase 1 inhibitor 6-O-butanoyl castanospermine (MDL 28,574) produced a significant delay in lesion development and reduced the amount of virus recovered from the brain. Virus load in the brains of mice, whose treatment started 2 days prior to infection, was reduced approximately 100-fold when compared to untreated controls. Treatment initiated at the time of infection, while less effective than pre-treatment, nevertheless reduced virus recovery from the brain by 10-fold. Consistent with its antiviral activity, orally administered MDL 28,574 was rapidly incorporated by brain tissue and mice fed with compound over extended periods maintained relatively high levels of drug at this site.

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SummaryMOL 74968 (9-[2-methylidene-3-(phosphonomethoxy)-propyl]guanine), a novel acyclonucleotide derivative of guanine, inhibited human immunodeficiency virus type 1 (HIV-1) replication in vitro with activity comparable to that of adefovir (PMEA; 9-(2-phosphonomethoxyethyl)adenine). MOL 74968 was investigated in combination with two licensed nucleoside analogues, zidovudine and didanosine, using a cell viability assay, and drug interactions were evaluated by the isobologram technique, by calculating combination indices and by the MacSynergyTM program. Inhibition of HIV-1 replication was only additive in both cases. MOL 74968 had equivalent antiviral activity against strains of HIV-1 HxB2 engineered to have mutations which conferred resistance to the nucleoside analogues lamivudine, didanosine and zidovudine and the non-nucleoside inhibitor of reverse transcriptase (RT) nevi rapine, as against the wild type strain. Continued passage of HIV-1 R F in C8166 cells in the presence of MOL 74968 for 5 months (30 passages) failed to select drug resistant mutants. Continued passage of virus in the presence of the same concentration of adefovir for the same length of time selected a virus in a single culture, which was 3-fold resistant to adefovir and cross-resistant to MOL 74968. Genotypic characterization of this virus revealed a lysine to arginine exchange (AAA to AGA) at position 65 in the RT gene. This virus was not cross-resistant to either zidovudine or nevirapine but

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