Novel Gamma-Secretase Inhibitor Shows Potential as Treatment for Alzheimer’s Disease

Novel Gamma-Secretase Inhibitor Shows Potential as Treatment for Alzheimer’s Disease

A promising new therapeutic target for treating Alzheimer’s disease has been identified by researchers at Rensselaer Polytechnic Institute’s Center for Biotechnology and Interdisciplinary Studies (CBIS).

The compound, named C1 by the researchers, has been shown to prevent the enzyme gamma-secretase from producing β-amyloid peptides in the brain.

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by the formation of amyloid plaques in the hippocampus and cerebral cortex in the brain. It has been hypothesized that the formation of the plaques eventually leads to cognitive decline.

C1 is a covalent inhibitor of gamma-secretase. C1 blocks the active site on the precursor protein which gamma-secretase binds to, thus preventing the enzyme from transforming the protein into amyloids. This gives C1 an advantage over other gamma-secretase inhibitors which inhibit activity by binding to the active site on the enzyme.

Since C1 binds to the precursor protein, it is unlikely to affect the normal functions of gamma-secretase. There have been trials of several drugs that block gamma-secretase, but they have resulted in severe side effects as the normal activity of the enzyme is disrupted. It is therefore hoped that C1 will be able to prevent the formation of amyloid plaques without the side effects of other gamma-secretase inhibitors.

Chunyu Wang, PhD, a professor of biological sciences at CBIS, has been screening compounds since 2018 to identify a potential drug that binds to the substrate protein. He used computer modelling to screen tens of millions of compounds. C1 was one of several potential gamma-secretase inhibitors to be identified from the screening. C1 was shown to block amyloid production in test tubes and cell culture with a high level of efficiency when present in micromolar concentrations.

“Our study provides the first proof-of-concept that targeting the C-terminal juxtamembrane lysines of APPTM is sufficient for reducing Aβ production, pointing to a new direction in AD drug discovery for reducing the amyloid load as disease-modifying therapy,” explained the researchers.

The work was supported by a grant from the Warren Alpert Foundation and the research is patent pending.

You can read more about the study in the paper – Substrate interaction inhibits γ-secretase production of amyloid-β peptides – which was recently published in the journal Chemical Communications. DOI: 10.1039/C9CC09170J

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