2. Academic Validation
  3. A C-Degron Structure-Based Approach for the Development of Ligands Targeting the E3 Ligase TRIM7

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

  • ACS Chem Biol. 2024 Jul 19;19(7):1638-1647. doi: 10.1021/acschembio.4c00301.
Christian J Muñoz Sosa 1 2,  Christopher Lenz 1 2,  Anton Hamann 1 2,  Frederic Farges 1 2,  Johannes Dopfer 1 2,  Andreas Krämer 1 2,  Veronika Cherkashyna 3,  Andrey Tarnovskiy 3,  Yurii S Moroz 3 4,  Ewgenij Proschak 1 5,  Václav Němec 1 2,  Susanne Müller 1 2,  Krishna Saxena 1 2,  Stefan Knapp 1 2
Affiliations

Affiliations

  • 1 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
  • 2 Structural Genomics Consortium, Buchmann Institute for Life Sciences (BMLS), Johann Wolfgang Goethe-University, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
  • 3 Enamine Ltd., Winston Churchill Street 78, 02094 Kyïv, Ukraine.
  • 4 Taras Shevchenko National University of Kyïv, Volodymyrska Street 60, Kyïv 01601, Ukraine.
  • 5 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
PMID: 38934237 DOI: 10.1021/acschembio.4c00301
Abstract

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.

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