't Hart Lab

RESEARCH

Concept

RNA-protein interactions (RPIs) play an essential role in a wide variety of cellular processes and therefore in diseases such as cancer, neurodegenerative disease, and heart disease. Knowledge on how to inhibit such interactions is required for selective modulation of cellular functions and will be valuable for the development of innovative therapeutics. However, general methods to identify inhibitors for RPIs are lacking and would provide the opportunity to unlock a wealth of novel therapeutic targets and strategies. We employ both genetically encoded libraries as well as structure-based design approaches to develop peptidic macrocycles as RPI inhibitors with novel modes of action.

Biology

Various aspects of RNA biology (of both coding and non-coding RNA) involve RNA-binding proteins (RBPs) for proper function. The group aims to develop selective inhibitors of various RBPs such as splicing factors, deadenylation factors, epigenetic modifiers, and others. Abnormalities in such process as mRNA splicing have been demonstrated as key drivers of oncogenesis and neurodegenerative diseases such as ALS. With potent and specific inhibitors in hand, the cellular mechanisms in which these RBPs play a role can be further elucidated and we can validate these RBPs as therapeutic targets.
 

Chemistry

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 therefore employ macrocyclic peptides to find suitable inhibitors. Recent advances in the understanding of the required properties for cell-permeability provide guidelines in the design and optimization of such structures. The lab works on a deeper understanding of these properties for future macrocycle design and optimization. In support of this goal, we also work on combining carbon-carbon bond forming chemistry with solid-phase peptide synthesis to have more control over peptide structure and properties. These projects aim to eliminate time and resource consuming amino acid synthesis procedures by installing a desired peptide modification at the end of a peptide synthesis route.