Heparinome routes toward novel drugs

Abstract

Heparin, a sulfated glycosaminoglycan composed of glucosamine and hexuronic acids in alternating sequence, binds a myriad of proteins collectively termed the “heparinome,” mainly through electrostatic interactions. Heparin prevents blood coagulation and is clinically applied to prevent thrombosis. The more sparsely sulfated polysaccharide heparan sulfate binds heparinome proteins more selectively, thereby regulating development, homeostasis, and disease. Biosynthesis of heparan sulfate yields products of variable, but controlled average composition. Dysregulation of heparinome interactions occurs in diseases, including cancer, inflammatory conditions, and amyloid diseases. Established structure–function relations provide a basis for drug development. The discovery of a specific pentasaccharide sequence in heparin, containing a rare glucosamine 3-O-sulfate group essential for anticoagulant activity, facilitated the development of various low-molecular-weight heparins with favorable pharmacokinetic properties. The 3-O-sulfate group has since been implicated in diverse aspects of heparan sulfate function. Heparin derivatives lacking anticoagulant activity can be administered at higher doses. Non-anticoagulant effects of heparin are increasingly exploited in the clinic, for instance, to curb the “cytokine storm” in severely ill COVID-19 patients. Other applications, such as in cancer and inflammatory conditions, are suggested by various incidental beneficial effects observed during heparin treatment for thromboembolic disease. Such effects are likely due to displacement of regulatory proteins from heparan sulfate proteoglycans at epithelial surfaces, or alternatively to inhibition of heparanase, a heparan sulfate-degrading enzyme. Exploitation in such cases would involve identification of key protein mediators followed by generation of minimally sulfated oligosaccharide drug candidates (or mimetics) with selective binding properties.

Keywords

Heparin / Heparan sulfate / Proteoglycans / Sulfation patterns / Polysaccharide–protein interactions / Anticoagulation

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