Invited
Modulating different components of the ubiquitin system with small molecules and cyclic peptides

The ubiquitin (Ub) signal plays crucial roles in various cellular activities such as cell cycle regulation, DNA damage repair, signal transduction, neural development and transcription. It is therefore not surprising that there is a great interest in targeting various components involved in the Ub pathway such as deubiquitinating enzymes (DUBs) and the 26S proteasome with the aim of producing drugs against several diseases. For nearly a decade my laboratory has been interested in developing chemical tools to assist in understanding Ub signaling in great details and allowing also for the development of novel modulators for its components. In particular, we have been interested in developing assays, activity based probes and inhibitors for DUBs, some of which I will present in this talk. In addition, I will describe our recent efforts to use the Random Non-Standard Peptides Integrated Discovery (RaPID) method to discover novel cyclic peptides that specifically bind Lys48-linked Ub chains. The discovered cyclic peptides found toprotected Lys48-linked Ub chains from DUBs activity and prevented proteasomal degradation of Ub-tagged proteins. We have also showed that these cyclic peptides could enter cells, inhibit growth and induce programmed cell death, opening new opportunities for therapeutic intervention.