Drug Discovery

Anti-tangle

Towards Pin1 Inhibitors in the Treatment of Alzheimer’s Disease

Investigator(s): Luc Buee PhD

Institution(s): French National Institute for Health and Medical Research (INSERM)

Duration: -

Summary:

Neurofibrillary tangles are one of the main brain lesions found in Alzheimer’s disease (AD). These lesions are believed by many scientists to cause the nerve cell death that causes AD. An abnormally phosphorylated protein, known as tau, is the major component of neurofibrillary tangles. It is believed that the abnormal hyperphosphorylation of tau causes tangle formation and the resulting nerve cell death. The enzyme Pin 1 is believed to play a role in the abnormal phosphorylation of tau. In AD brain Pin 1 is found within dying neurons where it is associated with large amounts of hyperphosphorylated tau. These Pin-1: tau complexes are aggregated to form tangles. Compounds that block Pin 1 activity are therefore, potential drugs for treating AD.The aim of this program is to screen an in silico (i.e. virtual) library of Pin-1 inhibitors and to use an in vitro assay to validate “hits” for inhibition of Pin-1 activity on tau phosphorylation. The work will be done in collaboration with CEREP, a combinatorial chemistry company based in Paris, France. If successful this program will discover novel anti-tangle compounds that after clinical development may be found efficacious in treating AD and other neurodegenerative diseases.