Transcript Document

Discussion 22
Inhibitors and Drugs
Questions
1.
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
tunicamine
uridine
O
HO
HO
OH
O
NH
H
AcHN
HO
N
10
O
O
HO
OH
OH
O
HO
N
OH
O
Fig. 50.2
O
O
NH
OH
NH
OH
H
N
HO
N
O
O
N
H
N
N
O
O
HO
HO
HO
H
HO
OH
O
O
HO
OH
O
50.3
HO
HO
OH
N
N
NH
O
HO
HO
OH
NH
NH N
H
N
O
O
O
PUGNAc
GlcNAcstatin
HO
HO
OH
O
N
S
CH3
NAG-thiazoline
Fig. 50.4
O
HO
HO
HO
O
HN
OH
N-propanoyl mannosamine
O
OAc
O
AcO
OAc
OAc
AcO
NH
N3
NH
O
N3
Ac4GlcNAz
N3
HN
OAc
OAc
AcO
H
N
O
OAc
N3
O
Ac4ManNAz
O
Ac4GalNAz
O
AcO
AcO
AcO
O
OH
N-aminolevulinoyl mannosamine
OAc
O
AcO
AcO
HN
HO
HO
HO
O
OAc
O
AcO
Ac5SiaNAz
CO2H
Fig. 50.5
O
N
HO
N
O
HO
N
H
DL-threo-PDMP
O
N
H
DL-threo-PPPP
Fig. 50.6
NANA
HO
DANA
OH
OH
O
AcHN
HO
OH
CO2H
4-amino-DANA
OH
OH
O
AcHN
OH
OH
OH
HN
NH
H2N
CO2H
O
AcHN
NH2
GS4071
GS4104
O
O
CO2H
O
AcHN
OH
OH
OH
4-guanidino-DANA
HO
CO2H HO
O
O
OC2H5
OH
AcHN
AcHN
NH2
NH2
Fig. 50.7
Figure 51.1. Examples of natural products possessing glycan components. Streptomycin
and erythromycin are antibiotics, doxorubicin is an anti-cancer drug and digoxin is used
to 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.