Glucosidase castanospermine

The importance of a basic nitrogen atom for strong inhibition by the indolizine type of inhibitor is demonstrated by the finding that I for inhibition by castanospermine A -oxide of the ) -D-glucosidase from almonds is 500-fold larger than of castanospermine itself (760 fiM V5. 1.5 /lA/at pH... 

Inhibition of D-Mannosidases and D-Glucosidases by Swainsonine and Castanospermine, Respectively... 

As a matter of fact, the second cycle increases the conformational rigidity of the molecule sometime increasing the activity and selectivity of the inhibitor. In the case of castanospermine for example, it has been postulated that the increase of inhibitory activity on a-glucosidase with respect to nojirimicin, is due to the orientation of the hydroxyl group at C-6 (referred to glucose) that in the case of castanospermine is restricted (Fig. 45).76... 

Castanospermine is a plant alkaloid isolated from the seeds of the Australian chestnut tree, Castanospermium australe. As with most anti-HIV inhibitors, the discovery of the compound predates the time of isolation of HIV-1. The compound inhibits a-glucosidase-1, and therefore normal processing of the glycopro-... 

Castanospermine (67) Indolizine alkaloid MX-3253 (formerly MBI-3253 Celgosivir 6-0-butanoyl castanospermine) (68) Antiviral [Hepatitis C virus (HCV)] Inhibits a-glucosidase I Phase 11 MIGENIX (received license from Virogen Ltd., UK) 577-581... 

Fig. 6. Superposition of ligands 1-deoxynojirimycin 2 (yellow, PDB 2J77) and castanospermine 8 (green, PDB 2CBU) bound to Thermotoga maritima p-glucosidase. The ring nitrogen atoms, all hydroxyl groups in the pyranoid rings, as well as 0-1 (8) and the primary 0-6 (2), respectively, are closely matched.

It is regrettable that Australian chemists failed to discover another local alkaloid, namely castanospermine 3. It was left to an overseas group to collect and extract the seeds from a Queensland legume to yield this valuable alkaloid [6]. Castanospermine seems to display a broad biological activity which surpasses even that of swainsonine, being a particularly powerful competitive inhibitor of both a- and -o-glucosidases [7]. The alkaloid is plentiful enough in the... 

Inhibitors can block the pathway at specific steps, causing the accumulation of biosynthetic intermediates. Castanospermine inhibits the a-glucosidase that removes the first glucose deoxymannojirimycin inhibits the a-mannosidase I that removes mannose from the Man8 intermediate, and swainsonine blocks the a-mannosidase II that removes mannose from the Man5 intermediate. In the presence of swainsonine, hybrid N-linked carbohydrates are synthesized. 

Alpha-1-antitrypsin mutations are associated with early-onset emphysema and liver disease that results in early death (50). The Z-variant of the disease is the most common and is present in over 95% of cases. This variant has been shown to be rescued in vitro by treatment with proteasome inhibitors (50). Several chemical and pharmacological chaperones have also been shown to correct the secretion of the mutant protein, which include the glucosidase inhibitor castanospermine, as well as the mannosidase inhibitors kifunensine (Fig. 2b)... 

Another common mechanism of correction is ER glucosidase inhibition (Fig. 1, star 2), which prevents the recognition of misfolded proteins by calnexin and calreticulin and presumably allows them to escape the ERQC. Inhibition of glucosidase with castanospermine and miglustat were shown to correct the trafficking of deltaE508 CFTR and alpha-l-antitrypsin (51, 61). Whether this mechanism also works on other ER-retained mutants remains to be determined. 

Castanospermine a-glucosidases (including amyloglucosidase, sucrase. maltase, isomaltase, trehalase, amylase, Glucosidase I and II) and p-glucosidases (including lactase and cellobiase), P-glucocerebrosidase and p-xylosidase ... 

However, castanospermine also inhibits the activity of lysosomal p-glucosidase and this affects the catabolism of glycosphingolipids. ... 

In addition to swainsonine, some of the other naturally-occurring polyhydroxylated alkaloids listed in Table 1 also show various anti-cancer properties. However, none of these compounds have been exploited to nearly the same extent as swainsonine. For example, the potent a-glucosidase inhibitor castanospermine (also an indolizidine alkaloid) has been reported to inhibit experimental metastasis in mice. ... 

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... 

In a Moloney murine leukemia virus assay that served as a model for HIV, it could be demonstrated that glucosidase inhibitors 1-deoxynojirimycin 2 and castanospermine 4 were active at concentrations of 1-2 p.g/ml [185]. 

Of nearly 50 iminosugars probed for antiHIV activity [183], five were active at subcytotoxic levels. In particular, the a-glucosidase inhibitors 1-deoxynojirimycin 2 and the plant alkaloid castanospermine 4 were confirmed to be active at concentrations between 0.1 and 0.5 mg/ml. Even more pronounced were the activities of 1-deoxynojirimycin derivatives with enhanced lipophilic character such as V-methyl- 70, V-ethyl- 71 and, in particular, V-butyl-1-deoxynojirimycin 72 in the same concentration range [183,186]. 

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