In vivo modulation of ubiquitin chains by N -methylated non-proteinogenic cyclic peptides

The attachment of ubiquitin and ubiquitin chains are critical
post-translational modifications. Diseases, like cancer, often
involve dysregulation of this ubiquitin system. Here, we
report the discovery of small, highly non-proteinogenic
cyclic peptides which can tightly bind and modulate
ubiquitin chains with particular Lys48-linkages. Our cyclic
peptides block the action of deubiquitinases and the
proteasome, induce apoptosis in vitro, and attenuate
tumor growth in vivo. We conclude that modulating
ubiquitin chains is a promising avenue for future
anti-cancer therapeutics.