We reported on the extension of conformational restriction, which was particularly successful in the field of peptidomimetics, to sphingolipids as another class of conformational^ flexible molecules. The major effect of this approach is the unexpected inhibition of glycosyltransferases that do not accept ceramide itself but instead accept glycolipids of more complex structure as substrates. Inhibitors are available for glucosylceramide synthase, a glycosyltransferase that accepts ceramide as substrate [8, 10]. This prodrug mechanism offers the possibility of modifying the lipid composition of cellular surfaces. A somehow related effect has been achieved by interference with carbohydrate metabolism. Analogs of N-acetyl-D-mannosamine are biosynthetically incorporated into sialic acids, which in turn are transformed into glycocolipids and glycoproteins of the cell surface and modify their properties like cell adhesion [48, 49]. This process is also known as cell-surface engineering [50].

Fig. 1.4.8. Concept for cell surface engineering: exogenously added ceramide analogs can lead to modification of the hydrophobic and the hydrophilic part of membrane sphingolipids and alter the properties of membrane proteins.

Because different glycosyltransferases bound to the membrane of the Golgi apparatus can be indirectly inhibited by ceramide-analogs at non-toxic concentrations, this should lead to modified glycolipid pattern (Figure 1.4.8) on cell surfaces and is the pharmacological equivalent to mice with the corresponding genetically engineered defects [9]. It has been shown that chemically modified ceramides are metabolized to glycolipids and to sphingomyelin [10]. These artificial metabolites should be transported to the plasma membrane where they can modify the activity of membrane proteins, similar to inhibition of glycosyltransferases in the Golgi apparatus. Neoglycolipids of this type might alter the colligative properties of microdomains or influence receptor activity as single molecules (Figure 1.4.8). In addition to the lipids mentioned in the introduction, glycosphingolipids can also drastically modify the activity of pharmacologically relevant receptors. For example, the receptors for insulin [51] and epidermal growth factor [52] are down-regulated by ganglioside GM3, and the activity of the nerve growth receptor is increased by ganglioside GM1 [53]. Therapeutic applications of this approach are reviewed elsewhere [10].

1.4.6 Outlook

Conformational restriction of ceramide led to the development of cell-permeable, indirectly acting inhibitors of glycosyltransferases. Together with other ceramide analogs [10, 36] this concept demonstrates that, in principle, it is pharmacologi cally possible to achieve effects comparable with those obtained in genetically engineered mice with glycosyltransferase deficiencies [9]. Further efforts are required to develop heterocyclic lipidomimetics by this approach.


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