Intracellular peptides as drug prototypes

Proteasome-processed functional intracellular peptides (InPeps) were recently described, suggesting the need for adapting our understanding of how cells build macromolecular signaling interactions. InPeps are distinct from antigens, cryptides and neuropeptides, having been initially identified in mammals by means of a substrate-capture assay that used inactive endo-oligopeptidases. InPeps modulate G-protein coupled receptor signal transduction, cell survival and energy metabolism after direct delivery within cells. In neurodegenerative diseases, for example, InPep profiles were modified in parallel with disease progression. Manipulation of oligopeptidase metabolic activity through knockdown, overexpression or genetic knockout animal models alters specific InPep profiles, with corresponding phenotypic alterations. InPep structure can also be modified to develop novel therapeutic drugs, as demonstrated here for the example of pep19. In this chapter, we review findings that precipitated the original discovery of InPeps as well as the rationale for use of InPeps as drug prototypes.