Discussion 22 Inhibitors and Drugs

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Discussion 22Inhibitors and Drugs
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Questions

• Explain how an inhibitor of glutaminefructose
  aminotransferase (GFAT) would affect
  glycosylation?
• From a mechanistic point of view, how can an
  alkaloid that inhibits a glycosidase also block a
  glycosyltransferase?
• Propose chemical modifications to make to
  galactose to create an inhibitor of
  sialyltransferases.
• How would you go about obtaining an inhibitor of
  glycans that are initiated by the addition of
  O-fucose to EGF repeats in Notch?
• 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. 
• 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.
• How can an enzyme inhibitor also act as a
  chemical chaperone?
• 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.  
• 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?
• Explain how increasing the extent of
  glycosylation of recombinant glycoproteins can
  increase their half-life in vivo.
• Describe the potential deleterious effects of
  producing recombinant therapeutic proteins in
  cultured animal cells of non-human origin.

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Fig. 50.1
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Fig. 50.2
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50.3
GlcNAcstatin
NAG-thiazoline
PUGNAc
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Fig. 50.4
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Fig. 50.5
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Fig. 50.6
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Fig. 50.7
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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.
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Figure 51.2. The synthetic influenza
neuraminidase inhibitors RelenzaTM and TamifluTM.
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Figure 51.3. Glycomimetic E-selectin inhibitors
based on sialyl Lewis X.