Synthesis of a Targeted Library of Heparan Sulfate Hexa‐ to Dodecasaccharides as Inhibitors of β‐Secretase: Potential Therapeutics for Alzheimer’s Disease

Abstract

Heparan sulfates (HS) are a class of sulfated polysaccharides that function as dynamic biological regulators of the functions of diverse proteins. The structural basis of these interactions, however, remains elusive, and chemical synthesis of defined structures represents a challenging but powerful approach for unravelling the structure-activity relationships of their complex sulfation patterns. HS has been shown to function as an inhibitor of the β-site cleaving enzyme β-secretase (BACE1), a protease responsible for generating the toxic Aβ peptides that accumulate in Alzheimer's disease (AD), with 6-O-sulfation identified as a key requirement. Here, we demonstrate a novel generic synthetic approach to HS oligosaccharides applied to production of a library of 16 hexa- to dodecasaccharides targeted at BACE1 inhibition. Screening of this library provided new insights into structure-activity relationships for optimal BACE1 inhibition, and yielded a number of potent non-anticoagulant BACE1 inhibitors with potential for development as leads for treatment of AD through lowering of Aβ peptide levels.

Pharmacology of Heparin and Related Drugs

“…However, heparin, HS, and heparin mimetics are observed to inhibit the production of Ab both in vitro (Patey et al, 2006) and in cortical cells (Cui et al, 2012). The relationship between HS fine structure, molecular weight, and anti-BACE-1 activity has been actively pursued (Patey et al, 2008;Arungundram et al, 2009;Cui et al, 2012) and has led to the development of promising lead compounds in the octasaccharide to decasaccharide size range; the repeating non-natural disaccharide sequences GlcNAc6S-GlcA2S and GlcNAc6S-IdoA2S are found to be particularly effective, with minimal anticoagulant side effects (Schwörer et al, 2013).…”

Extracellular matrix proteomics in schizophrenia and Alzheimer’s disease

“…Tau protein is involved in the formation of neurofibrillary tangles [93]. Studies have indicated roles of HSPGs and CSPGs in Alzheimer's disease [94-97]. HS has been shown to bind and affect aggregation, intracellular internalization and clearance of Tau and APP [98].…”

Chemoenzymatic synthesis of heparan sulfate and heparin

“…The 2-O-sulfation to form an IdoA2S residue is essential because it prevents further action of C 5 -epi on this residue and accelerates the C 5 -epimerization reaction. 47 These steps can be further repeated to form deca- (13) and dodecasaccharide (14) to introduce three and four repeats of IdoA2S-GlcNS disaccharides as described in a recent publication. 15 …”

“…Therefore, HS oligosaccharide synthesis can be completed by skilled synthetic chemists in a small number of highly specialized labs. [4][5][6][7][8][9][10][11][12][13] In recent years, a chemoenzymatic synthesis has emerged using glycosyltransferases, epimerase and sulfotransferases. 14,15 Compared to chemical synthesis, the chemoenzymatic approach offers shorter synthetic routes, excellent recovery yields, and utilizes a few common precursors for the preparation of diverse HS oligosaccharide structures.…”