The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

Abstract

This review comes as a part of the special issue “Emerging frontiers in GAGs and mimetics”. Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

Antiviral strategies should focus on stimulating the biosynthesis of heparan sulfates, not their inhibition

“…The core proteins on the cell surface are internalized by endocytosis after shedding (for transmembrane protein cores) or cleavage of the GPI bond (for glypicans) and degraded by a multistep process ending in the lysosomes [ 57 ]. This route of degradation of the core proteins by endocytosis is of particular interest to us since HPSE and heparinase (the enzymes responsible for the degradation of HS) have already been shown to inhibit the attachment to the cell surface of several viruses through several in vitro studies, explaining their role in viral entry.…”

Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management

“…Among HS modifying enzymes, HPSE is definitely one of the most investigated as a cancer drug target [ 105 , 175 , 185 , 188 , 203 , 204 ]. Early observations of the powerful HPSE inhibitory activity of heparin lead the way for the screening of heparin/HS mimetics as HPSE inhibitors [ 102 , 205 , 206 , 207 , 208 ].…”

“…Based on promising preclinical data, some HS-based therapies are currently under clinical investigation although none was yet approved [ 212 , 213 , 214 ]. Difficulties in interpreting data with HS mimetics are mainly due to their pleiotropic effects [ 160 , 206 , 207 ].…”

“…Heparin derivatives and HS mimetics are drawing great attention for developing new therapeutics for diverse diseases, from inflammation to neurodegenerative disorders and cancer [ 207 ]. HS mimetics overcome a problem known for more than half a century in Medicine related to heparin use.…”

Heparin and Its Derivatives: Challenges and Advances in Therapeutic Biomolecules

“…Among GAGs, HS is composed of D-glucosamine and hexuronic acid units with many sulfate groups in a molecular structure and shows good biocompatibility and biodegradability [ 2 ]. It is a biomaterial that is essential for normal embryonic development, cellular homeostasis, and various pathological processes as well as neurodegenerative diseases [ 3 , 4 , 5 ]. For example, abnormal heparan sulfate storage in lysosomes develops primarily mucopolysaccharidosis lll B [ 6 ].…”