Castanospermine immunodeficiency virus

Johnson VA, Walker BD, Barlow MA, Paradis TJ, Chou T-C, Hirsch MS. Synergistic inhibition of human immunodeficiency virus type 1 and type 2 replication in vitro by castanospermine and 3 -azido-3 -deoxythymidine. Antimicrob Agents Chemother 1989 33 53-57. 

A search for analogues of Castanospermine as inhibitors for human immunodeficiency virus (HIV)627 illustrates the use of lipases in organic solvents pioneered in Klibanov s laboratory.62 Castanospermine [333.1, Scheme 4.333J underwent selective esterification of the Cl hydroxyl function using subtilisin in pyridine. A second selective acylation of the C7 hydroxyl in 333.2 was accomplished with the lipase isolated from Chromohacterium viscosum (CV) to give the 1,7-di-w-butanoyl derivative 333J from which the Cl acyl function was selectively removed using subtilisin in aqueous media. 

Another therapeutic application of polyhydroxylated alkaloids is as anti-viral agents. Inhibitors of processing a-glucosidases, such as castanospermine and DNJ, have been shown to decrease the infectivity of human immunodeficiency virus (HIV) in vitro at concentrations which are not cytotoxic to lymphocytes, whereas specific inhibitors of processing a-mannosidases (swainsonine and 1-deoxymannojirimycin) have no effect on Castanospermine and DNJ also reduce the infectivity of other retroviruses... 

Castanosp ermine has been shown to have in vitro antiviral activity against human immunodeficiency virus (HIV) [99] and human cytomegalovirus (CMV) [100], which is an opportunistic pathogen in AIDS. Alterations in viral coat glycoproteins in the presence of castanospermine are associated with a loss of infectivity. 6-0-acyl derivatives of castanospermine are more potent inhibitors of HIV growth than the natural product with the 6-O-butyryl-derivative (MDL 28,374) currently in clinical trials for AIDS. The lipophilic nature of the acyl derivative improves uptake by cells but the compound appears to be intracellularly converted to castanospermine [101]. 

Three pivotal papers that appeared in 1987 established the potency of castanospermine in inhibiting the replication of human immunodeficiency virus-1 (HIV-1) (254-256), and the intense activity that succeeded these revelations was documented in the previous review (2). Castanospermine is recognized as being one of the most powerful inhibitors of HIV-induced syncytium formation (virus-induced cell fusion), a crucial feature in the cell-to-cell transmission of HIV infection (257). It subsequently transpired that esters of (+ )-239 were even more effective inhibitors of HIV replication, no doubt because their lipophilic nature facilitates penetration through cell membranes, after which they are probably hydrolyzed to the parent alkaloid (216). Much of the current activity centers on 6-... 

Castanospermine has been screened for efficacy against simian immunodeficiency virus (265), and has been shown to prevent syncytium formation in feline astrocyte cultures infected with the feline immimodeficiency virus by modifying the viral cell envelope (266). It suppressed syncytium formation and hemolytic activity in baby hamster kidney cells infected with Newcastle disease virus however, synthesis and cell surface expression of the hemagglutinin-neuraminidase glycoprotein in the viral envelope were not affected, which strengthens the hypothesis that poor transport of the parent alkaloid across membrane barriers may limit its therapeutic use (267). Both 239 and its 6-0-butanoyl ester had comparable relative toxicities and antiviral effects on Rauscher murine leukemia virus (268), but the ester was more potent than the parent alkaloid in inhibiting replication of Moloney murine leukemia virus (258). The ester was also active against herpes simplex viruses types 1 and 2 (269,270). In the latter case, conclusive evidence was provided for intracellular hydrolysis to 239. 

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