Synthesis, Structure, and Function of Heparan Sulfate Glycopolymers to Investigate Glycosaminoglycan–Protein Interactions

TL;DR

Scientists designed new heparan sulfate mimics to better target disease-related proteins, showing strong anti-cancer and protective effects in models.

Contribution

A novel glycopolymer-based approach to synthesize HS mimetics with precise structural control and multivalency for targeted HSBP interactions.

Findings

The synthesized glycopolymer showed superior potency and selectivity over existing HPSE inhibitors.

The glycopolymer demonstrated antimetastatic activity in mammary carcinoma and myeloma cancer models.

It protected pancreatic β-cells and human islets from HPSE-induced damage.

Abstract

Heparan sulfate (HS), a highly
sulfated glycosaminoglycan, varies
in its disaccharide units, chain length, and sulfation patterns. HS
structural diversity and its localization at cell surfaces and in
the extracellular matrix enable HS interaction with a breadth of HS-binding
proteins (HSBPs), HS thus being a co-receptor for other proteins and
initiating various biological responses. Several designed and studied
HS mimetics modulate HSBP activity implicated in various diseases.
A key HSBP is heparanase (HPSE), which can cleave HS into smaller
fragments, facilitating release of angiogenic growth factors, activating
biological signals that may contribute to pathological conditions
(promoting tumor development and metastasis), and enabling autoreactive
immune cells to target insulin-producing β-cells. Thus, HPSE
serves as a crucial target for disease therapy strategies. Several
saccharide-based HS mimetics, designed as HSPE inhibitors, have advanced
to clinical trials, but these sugar molecules were discontinued or
suspended due to adverse effects from off-target HSBP interactions.
Glycopolymers engineered to incorporate functionalized glycan residues
into their polymeric backbones are a promising approach to retain
endogenous HS’ native biological activity, thereby enhancing
therapeutic efficacy. Stereoselective formation of α-1,2-cis-glycosidic linkages that connect the glucosamine unit
to the uronic acid disaccharide core is challenging during development
of HS mimetics as HPSE inhibitors. Computational modeling and a stereoselective
catalytic glycosylation method were used to design and synthesize
glycopolymer-based HS mimetics with repeating units of the glucosamine–glucuronic
acid disaccharide core and a controlled degree of polymerization and
incorporate glycan residues with precisely tailored sulfation patterns.
This strategy ensures targeted biological activity and maintains structural
specificity toward its intended HSBP. Glycopolymers were synthesized
using ring-opening metathesis polymerization with the third-generation
Grubbs catalyst, enabling precise control over both the degree of
polymerization and molecular weight by tuning the catalyst loading.
The most potent glycopolymer displayed superior potency and selectivity
compared to previously reported monovalent and polymeric HPSE inhibitors
and demonstrated remarkable antimetastatic activity in models of mammary
carcinoma and myeloma cancer. It also protected pancreatic β-cells
and human islets from HPSE-induced damage, suggesting a possible diabetes
therapeutic agent. Prioritizing multivalency and precise structural
control in polymeric HS mimetics facilitates targeted interactions
with specific HSBPs and enhances their potential for precision therapeutic
applications.

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