In RNA-drugs we want to establish a platform to develop small molecules as drugs against viral RNA targets by a structure-guided drug development approach. After characterization of (secondary) RNA structures by NMR (Schwalbe) and other biophysical techniques (Schlundt) target sequences with high conservation in sequence and structure will be chosen. Screening of fragment libraries by NMR (Schwalbe) result in first generation compounds that then are refined to bind stronger, more specific and with better pharmaceutical properties.
To achieve this, different methods are used in parallel and subsequently. Bioinformatic analysis (Saverna) of the first screenings can provide second generation compounds with increased affinity to the target as well as improved pharmaceutical requirements. Derivatives of the first and second generation compounds are then synthesized (Göbel, Bracher, Merk, Schwalbe, Specs) and examined by NMR (Schwalbe), in-line probing (Göbel), DSF (Merk, Schwalbe), ITC (Merk, Schwalbe) and functional in-vitro and in-cell assays (Weigand, Schwalbe) to achieve a lead structure for the further development to a RNA-drug. With increasing knowledge of the interactions of viral RNA segments with viral or host proteins (Schlundt) the compounds and assays can be further optimized. Viral assays (Ciesek) will accompany and complete the platform to realize the aim of the Sprin-D challenge “Quantum leap for new antiviral compounds”.