Heparan sulfates (HS) are a class of sulfated polysaccharides which 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 beta-site cleaving enzyme �-secretase, a protease responsible for generating the toxic A-beta 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 dodeca-saccharides, targeted at �-secretase inhibition. Screening of this library has provided new insights into structure-activity relationships for optimal �-secretase inhibition, and yielded a number of potent non-anticoagulant inhibitors with potential for development as leads for treatment of AD through lowering of A-beta peptide levels.

Synthesis of heparan sulfate hexa- to dodecasaccharides as inhibitors of the Alzheimer's disease target �-secretase

246th National Meeting (2013)

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