CELL-SPECIFIC TARGETING OF FUSION PROTEINS THROUGH HEPARIN BINDING - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 399

(CS), dermatan sulfate (DS), heparan sulfate (HS), and
hyaluronan based on their sugar compositions. Except hya-
luronan, the other GAGs display modifications of sugar
molecules, consisting mostly of sulfated hydroxyl groups
and epimerization of sugar structures [5,6]. Compared to
KS, CS, and DS, HS contains the greatest number of
different modifications. Consequently, heparan sulfate pro-
teoglycans (HSPGs) have been suggested to be one of the
most information-condensed biological molecules in nature

[7]. In fact, HSPGs are highly specific "targets" for a wide
variety of proteins, growth factors, and viruses as shown
schematically in Figure 27.1.
In this chapter, the biochemical and regulatory mecha-
nisms on how HSPGs provide tissue-specific targeting as
well as how fusion proteins that bind to HSPGs can take
advantage of this natural targeting system will be described
as a rationale for developing targeted therapeutics for human
diseases.

FIGURE 27.1 Heparan-sulfate proteoglycans in body and organs. Heparan-sulfate proteogly-
cans (HSPGs) consist of long chains of negatively charged sulfated sugars called glycosamino-
glycans (GAGs) that are covalently attached to either secreted or membrane-bound proteins on the
cell surface of almost all cells in the body. Their diversity in structure allows selective binding and
concentration of proteins, such as growth factors and viral proteins through highly specific,
positively charged heparin-binding domains (shown in red) to target specific cell types located in
specific tissues. Once targeted to the cell surface, other portions of the protein are used to activate
receptors or to enter the cell, in the case of viruses.