11 February 2021

New approach to creating Alzheimer’s drugs helps identify two potential treatment leads

Scientists at the University of Sheffield have developed a new approach to creating drugs to treat Alzheimer’s disease which has identified two potential new therapies.

A 3D rendered image of a neuron cell network
  • A team of scientists have discovered two new compounds which are early leads for drugs to treat Alzheimer’s Disease
  • Unlike other treatments for this complex disease, the new compounds target multiple biological pathways involved in the development of Alzheimer’s Disease
  • Alzheimer’s Disease is the most common form of dementia and is responsible for 80 per cent of all dementia cases
  • The new approach could be used for other diseases with complex causes like cancer

Scientists at the University of Sheffield have developed a new approach to creating drugs to treat Alzheimer’s disease which has identified two potential new therapies.

As we live longer, all forms of dementia are increasing. Alzheimer’s Disease is the most common form of dementia, responsible for 80 per cent of cases, and is predicted to affect 150 million people worldwide in less than 30 years.

The new drug leads, discovered by a multidisciplinary team and led by scientists at the University of Sheffield, are able to target the three pillars that cause Alzheimer’s disease, and improve on previous approaches to developing new treatments for the debilitating disease.

The causes of Alzheimer’s Disease are complex, but it is known that two rogue versions of natural proteins are involved. The first, called beta amyloid (Aβ), triggers the formation of plaque around brain cells, preventing them from communicating properly. While the second, called Tau, forms toxic tangles inside the brain cell which stops it from transporting essential nutrients.

These two events are connected and scientists believe a third molecule, called PrP, is responsible as when it binds to the rogue Aβ it leads to the distinctive cognitive impairment and neurotoxicity seen in Alzheimer’s disease.

Together, Aβ, Tau and PrP are seen as the three pillars which cause Alzheimers disease. Yet, most recent drug trials for Alzeimers Disease have only targeted Aβ, by trying to prevent it causing plaques and inducing Tau to start tangling. This approach has so far proved to be unsuccessful.

The Sheffield team has identified two new drug leads that not only bind to Aβ, but block its interaction with PrP and disrupts the formation of Tau tangles.

Professor Beining Chen, Professor of Medicinal Chemistry at the University of Sheffield, said: “Over 50 million people are thought to be living with Alzheimer’s disease, despite recent clinical trials there have been no successful drug leads which target all three key players that cause this complex disease.

“Our project was aimed at tackling the tough challenges in drug discovery and this is our first breakthrough in using a multi-targeted approach to identify new leads against a multifactorial disease like Alzheimer’s. Not only have we developed a new approach to creating treatments for Alzheimer’s, we have identified two new drug leads.

“We are very pleased that this collective effort which has involved multiple academic and industrial partners has been so successful.”

The team was able to find these compounds through a multi-step molecular-sifting process. They began by using computer programs to search through thousands of molecules to identify promising drug leads. These then went through a combination of test tube experiments to find which compounds bound Aβ best, leading to six lead candidates that were then tested in stem-cell models.

These final tests filtered the results down to two compounds that targeted all three pathways involved in the development of Alzheimer’s disease. The team now hopes to gain funding to further their research by optimising these new compounds into drug candidates for pre-clinical and clinical studies.


Additional information 

Chemical Science - full paper

The University of Sheffield's Department of Chemistry

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