Insulin-Degrading Enzyme known for long, remains poorly understood. It is involved in the clearance of physiologically important peptides and found in both intracellular and extracellular compartments. IDE was named on the basis of its affinity for, and ability to degrade insulin. IDE is thus suspected to be involved in the physiopathology of diabetes. Indeed it mediates the degradation of insulin in subcutaneous and visceral adipose tissues in human. IDE has been also directly implicated in the degradation of Aβ peptide in vitro. Reduction-of-function mutations of IDE found in the GK rat, or KO of the gene in the mouse genome, result in elevated insulin levels and elevated levels of Aβ in the brain. Interestingly enough, the chronic elevation of insulin observed in these animals is associated with insulin intolerance and hyperglycemia, reminiscent of type-2 diabetes.

Alzheimer’s disease is a devastating neurodegenerative disorder concerning about 20 million people. Among key features is the progressive accumulation of amyloid peptide deposits. This leads to the loss of neurons, subsequent strong cognitive deficit, and finally death. Understanding the mechanism by which amyloid pathologically accumulates in the brain is crucial for the development of therapeutic strategies. Initially, the accumulation of amyloid was thought to be exclusively the consequence of increased production. Recently, pathways of elimination of amyloid peptides by metalloproteases such as insulin degrading-enzyme were discovered. It has been shown that pathological downregulation of this enzyme are correlated with the development of the pathology. Thus understanding the exact role of Insulin-Degrading Enzyme may lead to new possible therapeutic approaches.

Diabetes melittus is a life-threatening and highly prevalent disorder that, fundamentally, is characterized by impaired insulin signaling and targeting more than 300 million people worldwide. The goal of most anti-diabetic therapies is to improve insulin signaling, either by direct injection of insulin, by stimulating the secretion of insulin, or by activating the insulin receptor signaling cascade. Theoretically, it should be possible to reach the same goal by inhibiting Insulin-Degrading Enzyme-mediated insulin catabolism. Despite half a century of research on this and its involvement in insulin catabolism, the development of small molecule inhibitors of Insulin Degrading Enzyme has been an elusive goal.

Our objective is to produce well designed chemical probes to explore the role of this enzyme to untangle its role, taking into account the peculiar structure of this protein.