Intramembrane proteases as drug targets

Proteases are considered attractive drug targets. Various drugs targeting classical, soluble proteases have been approved for treatment of human disease. Intramembrane proteases (IMPs) are a more recently discovered group of proteolytic enzymes. They are embedded in lipid bilayers and their active sites are located in the plane of a membrane. All four mechanistic families of IMPs have been linked to disease, but currently, no drugs against IMPs have entered the market. In this review, I will outline the function of IMPs with a focus on the ones involved in human disease, which includes Alzheimer's disease, cancer, and infectious diseases by microorganisms. Inhibitors of IMPs are known for all mechanistic classes, but are not yet very potent or selective - aside from those targeting γ-secretase. I will here describe the different features of IMP inhibitors and discuss a list of issues that need attention in the near future in order to improve the drug development for IMPs.