Our most recent paper published in Protein Science in part funded by CAPSTONE_H2020. The result of a multi-year collaboration with Pharmaxis / Syntara, we describe a unique novel small molecule inhibitor of the enzyme Insulin Regulated Aminopeptidase (IRAP). IRAP is an enzyme with many critical biological functions, ranging from the regulation of adaptive immune responses to the regulation of oxytocin and vasopressin levels in the brain as well as fibrosis. In a surprising twist, the compound binds to the active site of the enzyme and locks it in an open-conformation, being ineffective in blocking the processing of some larger physiological peptide substrates. This compound constitutes the first IRAP inhibitor we know to target the active site that utilizes a conformation-specific mechanism of action, provides insight into the intricacies of the IRAP catalytic cycle, and highlights a novel approach to regulating IRAP activity by blocking its conformational rearrangements.
Open Access link here: https://lnkd.in/ddjbFpSt