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-γ-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.