Research - Peter 't Hart

Molecular Biochemistry

All aspects of RNA biology (of both coding and non-coding RNA) involve RNA-binding proteins (RBPs) for proper function. RNA-protein interactions (RPIs) are therefore critical regulators of diverse cellular processes, implicating them in the pathogenesis of diseases such as cancer, neurodegenerative disorders, and cardiovascular disease. Our research focuses on elucidating the molecular mechanisms governing RPIs and we employ biochemical, biophysical, and cell biology techniques to gain a deeper understanding. Furthermore, we develop ligands for RNA-binding protein to gain insights in how aberrant RNA processing can be corrected and to validate these targets for future therapeutic intervention.

Targeted modulation of RPIs holds significant potential for selective manipulation of cellular functions, offering a pathway to innovative therapeutic strategies. However, a lack of general methods to identify RNA-binding protein ligands hinders exploitation of the promising target class. To address this challenge, we employ both genetically encoded libraries, structure-based design as well as generative AI strategies to develop macrocyclic peptides as RPI modulators with novel modes of action. Macrocyclic peptides have proven themselves in the past as a successful class of compounds for the inhibition of protein-protein interactions (PPIs). RPIs are in many ways analogous to PPIs, and we have demonstrated that macrocyclic peptides can effectively be used for their inhibition as well. Our efforts are particularly focused on hydrocarbon-stapled peptides, recognized for their enhanced conformational stability and cellular permeability. Integrating cell permeability as a critical design parameter from the outset is central to our development pipeline, ensuring the translational potential of our RPI modulators.

Financially supported by: