't Hart Lab
The interest of the Hart lab are the interactions between non-coding RNAs and their protein binding partners. Knowledge on how to inhibit such interactions is required for selective inhibition of cellular functions and will be valuable for the development of innovative therapeutics. We have a particular interest in the role of these ribonucleoprotein complexes in epigenetic gene regulation. Our lab will develop assays to study these interactions and screen libraries to identify novel macrocyclic inhibitors of RNA-protein interactions. Furthermore, the lab also aims to understand the properties macrocycles require to have both high affinity as well as sufficient cell-permeability. By starting with peptidic macrocycles and systematically replacing segments with small molecule/natural product like fragments we will attempt to optimize affinity, stability and cell-permeability.
Non-coding RNAs have a variety of functions within the cell and often the assembly of ribonucleoprotein complexes is required for activity. The epigenetic regulatory histone-modifying protein complexes are bound by a variety of long non-coding RNAs to guide them to specific genetic sites. At these sites they modify chromatin structure to either activate or repress gene transcription. We will develop inhibitors of such RNA-protein interactions and employ them to study these mechanisms in a cellular context. Since RNA-protein interactions typically involve large interfaces we will use macrocycles to find potent inhibitors. Macrocycles have proven themselves in the past as a successful class of compounds for the inhibition of protein-protein interactions. Recent advances in the understanding of the desired properties for cell-permeability provide guidelines in the design and optimization of such structures.