Chemists make headway in Alzheimer's research
Ferrier Research Institute researchers have made a significant step forward in the search for a treatment for Alzheimer's disease.
Ferrier chemists have discovered a way to create cluster compounds for controlling the process that leads to generation of amlyloid plaques in the brain disease.
In 2013, the chemists synthesised a type of complex sugar for the same purpose, in challenging 55 step synthesis. The new approach to construct single-entity clusters reduces the number of reaction steps by half.
“We wanted to simplify the synthesis without losing the desired potency, which is quite challenging,” says project leader Dr Olga Zubkova. “The new products will be easier and cheaper to make, and allow us to prepare larger amounts for various testing.”
Through the joint project, Ferrier chemists Dr Zubkova and Professor Peter Tyler worked with Professor Jeremy Turnbull and Dr Scott Guimond from University of Liverpool to construct new heparan sulfate glycomimetics with critical functions that control the activity of the beta-secretase enzyme in the brain. This enzyme catalyses the first step in the generation of amyloid plaques in Alzheimer’s Disease.
“We designed and decorated a more simplified dendritic core by using multiple short, more readily synthesised fragments”, says Dr Zubkova. “Though we significantly simplified the structures we still saw impressive amounts of bioactivity.”
Dr Zubkova says this provides a highly desirable product that could be used in the development of new treatments.
“These molecules involve sophisticated chemistry processes and target enzymes extremely well, which is crucial for pharmaceutical application. It could be used in numerous treatments as the role of heparan sulfate becomes better understood.”
The research, published recently in prestigious international journal Angewandte Chemie, was supported by funding from the Ministry of Business, Innovation and Employment.
The team has prepared a large collection of the compounds, with approximately 80 new intermediates as well as 11 final products as pure single molecules, something not previously achieved by any research group in the world.
“Others have tried by attaching highly charged fragments to the core which leads to a very complex mixture”, says Dr Zubkova. “But we’ve done it differently—we attach the fragments first before we sulfate them. We have, for the first time, prepared single-entity compounds presenting polyvalent display of heparan sulfate saccharides. That’s a point of difference and what makes our compounds unique.”