期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 19, 期 21, 页码 6817-6823出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201204519
关键词
Alzheimer's; carbohydrates; glycosylation; heparan sulfate; synthesis
资金
- Biotechnology and Biological Sciences Research Council UK
- Medical Research Council UK
- BBSRC [BB/I004343/1, BB/D006325/1, BB/D525713/1] Funding Source: UKRI
- MRC [G117/423] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PPG2012B-25] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/D006325/1, BB/D525713/1, BBS/B/13047, BB/I004343/1] Funding Source: researchfish
- Medical Research Council [G117/423] Funding Source: researchfish
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 structureactivity relationships of their complex sulfation patterns. HS has been shown to function as an inhibitor of the -site cleaving enzyme -secretase (BACE1), a protease responsible for generating the toxic A 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 structureactivity 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 A peptide levels.
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