title: Inhibition of glycoprotein processing and HIV replication by castanospermine analogues.
abstract: Inhibitors of glycoprotein processing enzymes have been shown to have activity against HIV. Several analogues of the known glucosidase I inhibitor, castanospermine (CAST), were synthesized and evaluated for their inhibitory effect on glucosidases and for antiviral activity against Moloney murine leukemia virus (MOLV) and HIV-1. The most effective analogue was 6-O-butanoyl CAST (B-CAST, MDL 28,574) with an IC50 of 0.05 micrograms/mL against MOLV. A correlation between inhibition of glucosidase I and MOLV replication was observed. This analogue was further evaluated against HIV-induced syncytial formation in HeLa T4+ cells and against productive infection in JM cells infected with HIV 1 (GB8 strain). B-CAST showed an IC50 of 0.3 micrograms/mL in the HeLa T4+ assay, compared to CAST at 11 micrograms/mL. The compound also was more potent (IC50:0.15 micrograms/mL) than CAST (4-6 micrograms/mL) in JM cells. The antiretroviral activity of B-CAST was further confirmed in Friend leukemia virus (FLV) infection in mice. B-CAST showed equivalent activity to AZT and was more potent than CAST in inhibiting FLV-induced splenomegaly in mice. The data presented herein suggest the potential of these novel glucosidase inhibitors as anti-HIV agents.
authors.affiliation: Merrell Dow Research Institute, Cincinnati, Ohio 45215.
authors.forename: P S
authors.initials: PS
authors.lastname: Sunkara
authors.forename: M S
authors.initials: MS
authors.lastname: Kang
authors.forename: T L
authors.initials: TL
authors.lastname: Bowlin
authors.forename: P S
authors.initials: PS
authors.lastname: Liu
authors.forename: A S
authors.initials: AS
authors.lastname: Tyms
authors.forename: A
authors.initials: A
authors.lastname: Sjoerdsma
mesh_terms: D000818:Animals; D002460:Cell Line; D005622:Friend murine leukemia virus / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006678:HIV / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D007212:Indolizines / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008809:Mice, Inbred C3H; D014779:Virus Replication / Q000187:drug effects; D054836:Indolizidines
chemical_list: D006023:Glycoproteins; D006026:Glycoside Hydrolases; D007212:Indolizines; C037806:castanospermine; D054836:Indolizidines