Inhibition of the Ubiquitin Transfer Cascade by a Peptidomimetic Foldamer Mimicking the E2 N-Terminal Helix

The enzymatic cascades for ubiquitin transfer regulate key cellular processes and are the intense focus of drug development for treating cancer and neurodegenerative diseases. E1 is at the apex of the UB transfer cascade, and molecules inhibiting E1 have shown promising activities against cancer cell proliferation. Compared to small molecules, peptidomimetics have emerged as powerful tools to disrupt the protein-protein interactions (PPI) with less drug resistance and high stability in the cell. Herein, we harnessed the D-sulfono-gamma-AA peptide to mimic the N terminal helix of E2 and thereby inhibit E1-E2 interaction. Two stapled peptidomimetics, M1-S1 and M1-S2, were identified as effective inhibitors to block UB transfer from E1 to E2, as shown by in vitro and cellular assays. Our work suggested that PPIs with the N-terminal helix of E2 at the E1-E2 and E2-E3 interfaces could be a promising target for designing inhibitors against protein ubiquitination pathways in the cell.

Automated summary

The enzymatic cascades for ubiquitin transfer play a key role in regulating cellular processes and are the focus of drug development for cancer and neurodegenerative diseases. In this study, we used peptide mimetics to inhibit the interaction between E1 and E2, and identified two effective inhibitors for blocking ubiquitin transfer. Our findings suggest that targeting protein-protein interactions involving the N-terminal helix of E2 could be a promising strategy for designing inhibitors against protein ubiquitination pathways.