A C‑Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7

TRIM7 is a ubiquitin E3 ligase with key regulatory functions,
mediating
viral infection, tumor biology, innate immunity, and cellular processes,
such as autophagy and ferroptosis. It contains a PRYSPRY domain that
specifically recognizes degron sequences containing C-terminal glutamine.
Ligands that bind to the TRIM7 PRYSPRY domain may have applications
in the treatment of viral infections, as modulators of inflammation,
and in the design of a new class of PROTACs (PROteolysis TArgeting
Chimeras) that mediate the selective degradation of therapeutically
relevant proteins (POIs). Here, we developed an assay toolbox for
the comprehensive evaluation of TRIM7 ligands. Using TRIM7 degron
sequences together with a structure-based design, we developed the
first series of peptidomimetic ligands with low micromolar affinity.
The terminal carboxylate moiety was required for ligand activity but
prevented cell penetration. A prodrug strategy using an ethyl ester
resulted in enhanced permeability, which was evaluated using confocal
imaging.