A variety of recent research suggests that excess and dysregulation of conserved epitranscriptional RNA modifications are involved in the heredity of phenotypes such as mental or metabolic disorders. Therefore, selective manipulation of the epitranscriptome with small-molecule drugs is an emerging treatment option for such diseases, wherein, increased levels of m5C modification on small non-coding RNAs have been in particular linked to epigenetic transmission of the disease phenotype.
We aim to tackle the development of RNA-modifying enzyme inhibitors by contemporary techniques of the medicinal chemistry repertoire. See also Transregio 319 RMaP.
We focus particularly on the development of selective covalent inhibitors of RNA methyltransferases by utilizing the "Inverse Drug Discovery" approach, in which fragment-like molecules of low complexity with weak but activatable electrophiles serve as the starting point for the development of selective enzyme inhibitors.
Furthermore, high-throughput nanomole-scale late-stage functionalization allows us to synthesize large compound libraries comprising novel drug candidates. Starting from our recently identified methyltransferase targeting lead structures and a several-hundred-members in-house azide/alkyne library, the NanoSAR technology enables the generation of large drug-like libraries, which we investigate for inhibition and binding properties by comprehensive biophysical and functional methyltransferase assays.
Another transformative method of generating new lead structures we use is offered by DNA-encoded libraries (DEL). Here, individual drug candidates are tagged each with a unique DNA tag in gigantic (several billion molecules) combinatorial compound libraries, and after affinity selection against the drug target, enriched binder molecules can be identified by DNA sequencing.
In order to understand the effect of RNA modifications at the molecular level, we strive to develop spectroscopic techniques to characterize native RNA in solution for its structure and dynamics.
In cooperation with our industry partner CLADE GmbH, we use mid-IR AquaSpec™ to look deep into RNA molecules of our interest. Our completed projects for the technological advance of academic medicinal chemistry include the development of the tools: openDSF, FINDUS, BANDIT, and ITCcalc.
