1. RNA as a drug target
Supervisor: Peter Lukavsky, Dr. rer. nat.
RNA is an attractive drug target with enormous potential for future treatment of systemic and cancer-related pathologies. Yet, most of the currently applied and developed small molecule therapeutics for cancer and systemic diseases target proteins. Interestingly, from 20000 human protein-coding genes (1.5% of the human genome) only 2000-3000 genes are considered to be disease-related. In this context, small molecule drug therapies target less than 700 genes which represents less than 0.05% of the genome. While the portion of protein-coding information in the genome is minor, the ENCODE consortium has proposed that more than 75% of our genome is transcribed into RNAs. This also includes large non-coding regions of mRNAs, namely 3’UTRs which contain many regulatory elements important for spatio-temporal regulation of gene expression, such as translational control, RNA transport and localization and mRNA decay. We propose to target non-coding mRNA elements with small molecules to alter gene expression. We will focus on cancer-related genes, where protein targets often lack druggable elements and therefore targeting them on the mRNA level is an attractive alternative. Our research aims to identify functional mRNA motifs that can bind small molecules and to reveal common small molecule scaffolds which interact with similar 3D RNA structures and thus form a basis for rational lead optimization.
- Nagel et al, EMBO Reports, 2016, 17, 1516.
- Di Giorgio et al, Med. Chem. Commun., 2019, 10, 1424.
- Warner et al, Nat. Rev. Drug Discov., 2018, 17, 547.
Requirements on candidates:
We are looking for highly motivated PhD candidates with background in biochemistry and biophysics who share our fascination for RNAs regulating gene expression.
Keywords: 3'untranslated region; small molecule drugs; RNA as drug target; cancer; high-throughput screening; RNA-based pulldown; translational control; mRNA decay, RNA-protein interactions; NMR spectroscopy; structural biology