Adapted from Purdue University
A molecule designed by a Purdue University researcher could lead to the first drug treatment for Alzheimer's disease.
"There are many people suffering, and no effective treatment is available to them," said Arun Ghosh, the Purdue professor who designed the molecule. "There is an urgent need for a drug to treat this devastating disease, and the scientific community has been working on this problem for many years."
The new molecule prevents the first step in a chain of events that leads to amyloid plaque formation in the brain. The material at various stages of plaque formation is made up of fibrous clumps of toxic proteins that cause the devastating symptoms of Alzheimer's disease, said Ghosh, who has a dual appointment in the chemistry and medicinal chemistry and molecular pharmacology departments.
"Interdisciplinary research and the tools available today allowed us to build a molecule that is both highly potent and highly selective, meaning it does not affect other enzymes important to brain function," he said.
Jordan Tang, head of the Protein Studies Research Program at the Oklahoma Medical Research Foundation, is one of the discoverers of the critical enzyme and target for intervention, Ghosh said.
Tang discovered a key enzyme called memapsin 2, or beta-secretase, that is involved in the development of Alzheimer's disease. The action of this enzyme on a special protein, called the amyloid precursor protein, leads to the formation of plaques in the brain. The development of an inhibitor compound targeting memapsin 2 could block this reaction, thus preventing the disease. Utilizing Tang's information about the enzyme, Ghosh designed the first memapsin 2 inhibitor.
"This is the most exciting target today for Alzheimer's disease intervention," said Tang, who holds the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation. "These interactions happen at a very early stage in the disease, and if we could block them, we could prevent many of the harmful steps that follow and drastically reduce the impact. In our most recent tests, a single dose of the designed compound reduced the beta-amyloid level by 30 percent."
Ghosh's team developed a novel structure-based design strategy to systematically understand where and how to target memapsin 2 specifically.
"According to our studies, inhibition of memapsin 2 does not cause toxic side effects," Tang said. "This is extremely encouraging because it allows for intervention very early in the stages of the disease, and it is a type of enzyme with which we are very familiar. There is a precedence of great success in this type of work."
A drug from the memapsin 2 inhibitor could go into the first phase of clinical trials this year and begin the lengthy trial process necessary before the FDA approves a drug to be available on the market.