Engineered heparins: novel beta-secretase inhibitors as potential Alzheimer's disease therapeutics

Cleavage of beta-amyloid precursor protein (APP) by the protease beta-secretase (BACE1) is a key step in beta-amyloid peptide processing. We have described a novel role for heparan sulphate polysaccharides in Alzheimer's disease pathology as naturally occurring inhibitors of beta-secretase, suggesting new avenues for discovery of novel drugs for Alzheimer's disease based on heparins.

To evaluate engineered heparin analogues as novel beta-secretase inhibitors in vitro, including modifications to increase bioavailability.

We tested a number of selectively desulphated and chemically modified heparins for their ability to inhibit BACE1 and other proteases in vitro using APP fluorescent resonance energy transfer peptide substrates

Several lead compounds have been identified that are effective beta-secretase inhibitors, but have negligible activity as anticoagulants or as inhibitors of other aspartyl proteases structurally related to beta-secretase. In addition, the compounds studied also give some insight into the structural interaction between beta-secretase and heparin, indicating that the structure of the polysaccharide is much more important than charge.

We have demonstrated that modifications to increase bioavailability of chemically modified heparins have little effect on their efficacy as beta-secretase inhibitors. Therefore, these heparins show promise for development as a novel class of pharmaceuticals that target the underlying pathology of Alzheimer's disease. We have also found further evidence that it is the structure of the polysaccharide that is important for the interaction with beta-secretase, not simply the level of sulphation or charge.