Prof. W. Velema: "Chemical Tools for RNA"

Organisch-chemisches Kolloquium

The Institute of Organic Chemistry invites to the lecture of

Prof. Dr. Willem Velena, Radboud University Nijmegen

who will be talking about

"Chemical Tools for RNA"

Abstract:

RNA is a highly versatile molecule and exhibits many diverse functions. Our lab explores new approaches and chemistries to study RNA structure and druggability. Our interests lie at the intersection of nucleic acid chemistry and antimicrobial research.

During this talk, new chemical tools are presented that can selectively modify biologically relevant RNA molecules in cells to aid in elucidating RNA structure. For example, our newly devised method Spatial 2′-Hydroxyl Acylation Reversible Crosslinking (SHARC) allows to measure nucleotides in close proximity in cellular RNA, which establishes a strategy for measuring RNA 3D distances and alternative conformations in their native cellular context.

Furthermore, using customized affinity-based profiling tools we study RNA structural folding and small molecule ligand binding to bacterial RNAs to explore these as antibacterial targets. We can determine ligand binding sites with single nucleotide resolution. Combining our tools with qPCR allows us to measure binding of RNA targeting drugs in live cells.

We explore new possibilities for antibacterial antisense therapies. Using small-molecule uptake tags inspired by endogenous iron-binders known as siderophores, we can effectively transport large antisense oligomers into bacteria and selectively down regulate protein production of essential genes.

Finally, the use of fluorogenic sensors allows for studying nucleic-acid processing enzymes. Here we present a quenched size-expanded nucleotide that can be used to investigate the polymerase TdT. The probe is capable of measuring real-time polymerase activity both in vitro and in live cells, which could find application in diagnostics. Application in a pilot high-throughput screen resulted in the identification of a non-nucleoside TdT inhibitor.