Glycobiology:

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Glycobiology Applications to drug development
Professor Carolyn R. Bertozzi Departments of
Chemistry and Molecular and Cell Biology HHMI
and UC Berkeley
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Cell surface oligosaccharides are determinants of
cell recognition
glycoprotein
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Two examples of carbohydrate-mediated
disease processes and strategies for therapeutic
intervention 1. Influenza virus infection 2.
Inflammation
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The influenza virus has two membrane-associated pr
oteins, hemagglutinin and neuraminidase
Neuraminidase cleaves sialic acid (enzyme)
Hemagglutinin binds sialic acid (receptor)
Host cell
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Life cycle of the influenza virus
SA
Hemagglutinin binds sialic acid to initiate
infection
SA
SA
SA
Host cell
SA
SA
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Sialic acid analogs inhibit hemagglutinin
and block influenza virus infection

Neuraminidase
Sialic acid
Hemagglutinin
Cell
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Enzymes catalyze reactions by preferential
binding of the transition state vs the ground
state
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Design of transition state analog neuraminidase
inhibitors

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Structure-based design of more potent and
selective neuraminidase inhibitors
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Two examples of carbohydrate-mediated
disease processes and strategies for therapeutic
intervention 1. Influenza virus infection 2.
Inflammation
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A hallmark of inflammation is the recruitment of
leukocytes from the bloodstream into surrounding
tissues
Tissue
Blood vessel
Leukocyte
Endothelial cells of the blood vessel
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The attachment of leukocytes to endothelial
cells at sites of inflammation is mediated by the
selectins
Leukocyte
L-selectin
E-selectin
P-selectin
Endothelial cell
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Inflammatory conditions involving the
selectins 1. Rheumatoid arthritis 2. Asthma 3.
Transplant rejection 4. Psoriasis 5. Inflammatory
bowel disease 6. Ischemia/reperfusion injury 7.
Diabetes 8. Multiple sclerosis 9. Many more..
Inhibitors of selectin-mediated cell adhesion
would be broad spectrum anti-inflammatory agents
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Sialyl Lewis x binds weakly to all three
selectins in vitro (Kd 1-2 mM)
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Soluble sialyl Lewis x is a potential
anti-inflammatory drug
Sialyl Lewis x
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Limitations of sialyl Lewis x as a therapeutic
agent Lack of potency Poor
pharmacokinetics Difficult and expensive
synthesis
Possible solutions Glycomimetics
Oligomerization Glycoprotein constructs
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(Novartis)
(Texas Biotechnology)
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Limitations of sialyl Lewis x as a therapeutic
agent Lack of potency Poor
pharmacokinetics Difficult and expensive
synthesis
Possible solutions Glycomimetics
Oligomerization Glycoprotein constructs
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Approaches to selectin inhibitors inspired by the
discovery of their biological ligands
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Structure of the biological selectin ligands
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Nagy and coworkers
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Kiessling and coworkers
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Limitations of sialyl Lewis x as a therapeutic
agent Lack of potency Poor
pharmacokinetics Difficult and expensive
synthesis
Possible solutions Glycomimetics
Oligomerization Glycoprotein constructs
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Development of a glycoprotein drug based on a
biological selectin ligand
Features Good potency (Kd 300-800 nM) Good
PK (t1/2 2-3 wks) conferred by the IgG Fc
region
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Structure of the biological selectin ligands
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Structure of the endothelial oligosaccharides that
bind L-selectin in vivo
Leukocyte
6-Sulfo sialyl Lewis x
L-Selectin

Endothelial cell
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Take home messages Carbohydrate-based drugs
are used to treat influenza Carbohydrates are
in clinical trials for inflammation Many new
companies have formed based on carbohydrate
technologies