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2016 Grants - Tautz
Novel Screening Platform to Identify Specific Inhibitors of STEP
Lutz Tautz, Ph.D.
Sanford-Burnham Medical Research Institute
La Jolla, CA
2016 Collaboration 4 Cure (C4C) Grant
Can a new nerve cell testing system identify drug candidates that inhibit a specific protein involved in Alzheimer’s disease?
The amount and activity of a protein known as STriatal-Enriched protein tyrosine Phosphatase (STEP) is higher in the brains of people with Alzheimer’s disease. Abnormal activation of STEP can interfere with nerve cell function and may contribute to the development or progression of Alzheimer’s disease. Recent studies have found that reducing STEP activity in Alzheimer’s-like mice can improve their cognitive abilities. Taken together this suggests that molecules that inhibit STEP may provide a new treatment option for Alzheimer’s, but it has been difficult to identify specific STEP inhibitors using traditional methods. Because the chemical structure of STEP is very similar to other proteins, it is challenging to identify molecules that only inhibit STEP while not interfering with the function of other normal proteins.
Dr. Lutz Tautz and colleagues have proposed a new high-throughput screening approach to finding drug-like molecules that specifically inhibit STEP. This technology is highly sensitive and may be able to detect specific STEP inhibitors not detected by conventional methods. Various drug-like molecules will be added to nerve cells growing in a laboratory dish to determine which compounds interfere with STEP activity. The goal of this work is to scale up the assay to test 10,000 compounds and rapidly identify drug-like inhibitors of STEP for further investigation. The most promising compounds will be tested for their ability to inhibit STEP in nerve cells from people with Alzheimer’s disease.
The novel methods being used in these studies could lead to the identification of drug candidates that specifically block abnormal STEP activity which could, in turn, help preserve nerve cell function. This is the first step in the development of novel therapeutics to slow, halt or prevent Alzheimer’s disease.