The development of chemical probes to study rhomboid proteases

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Rhomboids are a recently discovered family of intra-membrane serine proteases that residewithin a lipid bilayer and cleave specific proteins in their trans-membrane region. In turn, thecleaved protein is released and can act as an inter- or intracellular signal.Interestingly, rhomboid genes are found in many diverse organisms and are conservedthroughout evolution. However, only the first clues to their cellular roles have been uncovered.Detailed knowledge about their substrate specificity and functional roles in specific types ofcells and tissues is also lacking.The available chemical tools that have been used to study protease function areincompatible with rhomboids, possibly due to the exclusive nature of intra-membraneproteolysis. Here, a plan is proposed to develop and validate small molecules that selectivelytarget rhomboids. The design of these molecules is based on previous work on smallmolecule probes for soluble proteases, comprising of a covalent modifier and a peptide-likebinding element to influence selectivity. Here, we will combine serine protease reactivegroups with helical-inducing elements that can direct the probes to the membraneenvironment and the active site of the rhomboid protease. We will apply these molecules inthe study of the functional role of rhomboid in bacterial and mammalian systems, particularlyfocusing on cell communication processes.