Macrocyclic IDE inhibitors identified by an innovative protein-templated screening method to treat metabolic diseases and its complications – MACPROMEDIC

Insulin degrading enzyme (IDE) is a zinc metalloprotease that hydrolyses insulin and other amyloidogenic peptides. Besides, IDE is not limited to its proteolytic activity and acts also as a partner in protein quality control mechanisms. With all of these proteolytic and non-catalytic roles, IDE is linked to various disease states and more particularly in type 2 diabetes and its comorbidities such as diabetic foot ulcer, two pathologies with an unmet medical need. In order to unwind the different biological functions of IDE linked to its diverse substrates, it is essential to develop substrate-selective modulators. MACPROMEDIC aims for the design and the synthesis of new selective macrocyclic IDE inhibitors using the in situ macrocyclization. This original screening tool allow to discover various macrocycles of distinct nature and size that fit several discrete IDE conformers and furnish an unprecedented mean to give selective ligands for therapeutic applications.