To this point, efforts to develop therapeutic peptides for intracellular applications
were guided by the perception that unmodified linear peptides are highly unstable and therefore
structural modifications are required to reduce proteolytic breakdown. Largely, this concept
is a consequence of the fact that most research on intracellular peptides hitherto has focused
on peptide degradation in the context of antigen processing, rather than on peptide stability.
Interestingly, inside cells, endogenous peptides lacking any chemical modifications to
enhance stability escape degradation to the point that they may even modulate intracellular
signaling pathways. In addition, many unmodified synthetic peptides designed to interfere
with intracellular signaling, following introduction into cells, have the expected activity demonstrating
that biologically relevant concentrations can be reached. This review provides an
overview of results and techniques relating to the exploration and application of linear, unmodified
peptides. After an introduction to intracellular peptide turnover, the review mentions
examples for synthetic peptides as modulators of intracellular signaling, introduces endogenous
peptides with bioactivity, techniques to measure peptide stability, and peptide delivery.
Future experiments should elucidate the rules needed to predict promising peptide candidates.