A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7.
Christian J Muñoz SosaChristopher LenzAnton HamannFrederic FargesJohannes DopferAndreas KrämerVeronika CherkashynaAndrey TarnovskiyYurii S MorozEwgenij ProschakVáclav NěmecSusanne MüllerKrishna SaxenaStefan KnappPublished in: ACS chemical biology (2024)
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.
Keyphrases
- cancer therapy
- cell death
- oxidative stress
- small molecule
- single cell
- high resolution
- sars cov
- signaling pathway
- stem cells
- drug delivery
- endothelial cells
- cell therapy
- mesenchymal stem cells
- ionic liquid
- photodynamic therapy
- drug release
- mass spectrometry
- raman spectroscopy
- genetic diversity
- smoking cessation
- capillary electrophoresis