Single-Entity Heparan Sulfate Glycomimetic Clusters for Therapeutic Applications

• Published in: Angewandte Chemie International Edition 2015-02, Vol.54 (9), p.2718-2723
• Main Authors: Tyler, Peter C., Guimond, Scott E., Turnbull, Jeremy E., Zubkova, Olga V.
• Format: Article
• Language: English
• Subjects: Accessibility; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Carbohydrate Conformation; Clusters; dendrimers; Dendritic structure; Displays; Dose-Response Relationship, Drug; Exploitation; glycomimetics; Heparan sulfate; Heparitin Sulfate - chemical synthesis; Heparitin Sulfate - chemistry; Heparitin Sulfate - pharmacology; Humans; Inhibitory Concentration 50; oligosaccharides; Saccharides; Structure-Activity Relationship; Sulfates; Synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201410251

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan with a variety of critical functions in cell signaling and regulation. HS oligosaccharides can mimic or interfere with HS functions in biological systems; however, their exploitation has been hindered by the complexity of their synthesis. Polyvalent displays of small specific HS structures on dendritic cores offer more accessible constructs with potential advantages as therapeutics, but the synthesis of single‐entity HS polyvalent compounds has not previously been described. Herein we report the synthesis of a novel targeted library of single‐entity glycomimetic clusters capped with varied HS saccharides. They have the ability to mimic longer natural HS saccharides in their inhibition of the Alzheimer’s disease (AD) protease BACE‐1. We have identified several single‐entity HS clusters with IC50 values in the low‐nanomolar range. These HS clusters are drug leads for AD and offer a novel framework for the manipulation of heparan sulfate–protein interactions in general. A four‐legged copycat: Heparan sulfate (HS) has a variety of critical functions in cell signaling, but the exploitation of HS oligosaccharides as mimetic agents has been hindered by the complexity of their synthesis. Polyvalent displays of specific HS structures on dendritic cores are more accessible constructs (see example). Such HS glycomimetic clusters mimicked natural HS saccharides in their inhibition of the Alzheimer's disease protease BACE‐1.