Importance of protein-sugar interactions

The majority of marketed pharmaceuticals are based on modifying interactions between proteins and small molecules or modifying protein-protein interactions. Development of monoclonal antibodies (mAbs) has improved the ability to modulate protein-protein interactions.

A number of key proteins regulating inflammatory and other disease processes bind to specific carbohydrate structures, namely the glycosaminoglycans (GAGs). Such protein-GAG interactions are key in modulating protein function in vivo. Members of the GAG family include heparan sulfate (HS), chondroitin sulfate (CS), keratan sulfate (KS), and heparin. Heparin is a heterogeneous mix of sugars which has been marketed for its anti-thrombolytic properties for over 40 years. Heparin and more recently introduced low molecular weight heparins (LMWHs) work by binding to proteins such as anti-thrombin III, thereby modifying the activity of the protein in coagulation cascades in vivo. GAGs are located mainly on cell surfaces and in the extracellular matrix where they exert their biological function.

They do this by binding and modulating the structure of a multitude of proteins like growth factors, chemokines, metalloproteinases, etc. Therefore, each eukaryotic cell surface contains a specific set of proteoglycans with several GAG chains attached which represent (co-)receptors for various GAG binding proteins. Consequently, a cell surface resembles not a smooth membrane with protein islands but is covered by a network of glycan structures which themselves interact in a functional way with GAG binding proteins (see graph on the left).

Rather than using carbohydrate-based compounds to target these key protein-glycan interactions, ProtAffin is pioneering the field by using modified proteins to interfere with such protein-sugar interactions.

Download: GAG-protein review