Discussion 22Inhibitors and Drugs

Questions1. Explain how an inhibitor of glutamine:fructose aminotransferase (GFAT) would affect

glycosylation?2. From a mechanistic point of view, how can an alkaloid that inhibits a glycosidase also

block a glycosyltransferase?3. Propose chemical modifications to make to galactose to create an inhibitor of

sialyltransferases. 4. How would you go about obtaining an inhibitor of glycans that are initiated by the

addition of O-fucose to EGF repeats in Notch?5. Design a glycan-based therapeutic that acts by blocking the interaction of a naturally

occurring glycan with glycan-binding proteins on an intact (or live) microbe. 6. Identify at least two enzymes that might be targets for designing inhibitors of

selectin-mediated cell adhesion and propose a strategy for obtaining selective inhibitors.

7. How can an enzyme inhibitor also act as a chemical chaperone?8. The binding affinity of hemagglutinin to monomeric sialic acid is very weak, with a Kd

in the millimolar range. Explain how influenza virus manages to bind to host cells with very high avidity despite the weak affinity of its receptor for sialic acid.  

9. A portion of erythropoietin (EPO) produced by CHO cells is not full sialylated (i.e., some glycoforms have exposed galactose residues on their N-glycans). What sugars might be added to the cell culture media to increase the overall level of EPO sialylation?

10. Explain how increasing the extent of glycosylation of recombinant glycoproteins can increase their half-life in vivo.

11. Describe the potential deleterious effects of producing recombinant therapeutic proteins in cultured animal cells of non-human origin.

Fig. 50.1

Fig. 50.2

GlcNAcstatin

50.3

NAG-thiazolinePUGNAc

Fig. 50.4

Fig. 50.5

Fig. 50.6

Fig. 50.7

Figure 51.1. Examples of natural products possessing glycan components. Streptomycinand erythromycin are antibiotics, doxorubicin is an anti-cancer drug and digoxin is usedto treat cardiovascular disease.

Figure 51.2. The synthetic influenza neuraminidase inhibitors RelenzaTM and TamifluTM.

Figure 51.3. Glycomimetic E-selectin inhibitors based on sialyl Lewis X.