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2016 Grants - Wagner
Screening for Novel Gamma-Secretase Modulator Scaffolds
Steven Wagner, Ph.D.
University of California, San Diego
La Jolla, CA
2016 Collaboration 4 Cure (C4C) Grant
Can molecules with unique chemical structures be found that modulate the gamma-secretase protein and reduce toxic beta-amyloid production?
The protein fragment beta-amyloid can form clumps called plaques, a hallmark of Alzheimer’s disease. Beta-amyloid is produced from its parent protein by the cutting action of a series of proteins including one known as gamma-secretase. Scientists have developed numerous compounds that inhibit gamma-secretase, but because gamma-secretase has other important functions, these potential drug candidates have had unacceptable side effects. The focus has now turned to discovering new compounds called gamma-secretase “modulators” (GSMs) that work by specifically preventing the ability of gamma-secretase to produce toxic beta-amyloid without interfering with its other normal functions. However, current GSMs all share a common chemical structure or “scaffold” raising the possibility that if one GSM causes unwanted side effects, then all of the other GSMs with the same scaffold could as well. Discovering new GSMs with novel chemical structures may increase the chances of finding an effective treatment for Alzheimer’s disease.
Dr. Steven Wagner and colleagues have proposed studies to discover new GSMs with a variety of different chemical structures. The researchers will use high-throughput screening assays to test more than 360,000 drug-like molecules. The compounds will be added to nerve cells growing in a laboratory dish to determine which molecules most effectively reduce the amount of specific forms (Aβ42) beta-amyloid. Drug-like molecules that are found to reduce Aβ42 production will be further examined to ensure that their structure is sufficiently different from existing GSMs and that they will be able to cross from the blood stream into the brain.
The novel methods used by Dr. Wagner and his team could lead to the rapid identification of new molecules with the potential for drug development. Discovery of GSMs with diverse chemical structures will increase the likelihood that this class of drugs can be successfully developed as new treatments to slow, halt, or prevent Alzheimer’s disease.