First PREP inhibitors were synthesized already on early 1980s, and typically, these compounds were designed to inhibit the capability of PREP to cleave short peptides as effectively as possible. The idea behind this was that by inhibiting PREP, one could elevate peptide levels in brain and this could have beneficial effects on memory. This hypothesis was tested in various preclinical models, and Servier's S17092 even in phase II clinical trials on memory but the results were controversial.
When PREP lab discovered that novel functions of PREP, such as inducing alpha-synuclein aggregation and induction of autophagy, are based on protein-protein-interactions, we wanted to test what kind of PREP inhibitor structures would be optimal for these effects. To our surprise, it turned out that some very potent PREP inhibitors did not have any effects on alpha-synuclein aggregation and autophagy but some weak inhibitors had very good impact. It appears that typical PREP inhibitors are not optimal for protein-protein-interaction based effects (and vice versa), and we suggest in our recent paper that this opens completely novel possibilities for PREP inhibitor development.
Full-text publication is available at journal site: https://www.sciencedirect.com/science/article/pii/S0753332220304455?via%3Dihub