The development of new drugs against the SARS-CoV-2 virus is in the focus of the research project “Conserved RNA elements as novel drug targets for antiviral therapy (Target-RNAantiV)“ supervised by PD Dr. Julia Weigand at the Technical University of Darmstadt. The Volkswagen Foundation is supporting this and 11 other projects in Germany within their funding initiative “Viral Zoonosis – Innovative Approaches in Drug Development” with 7 million Euro.
With only minor infrastructural requirements necessary to distribute drugs worldwide, they are an important tool to prevent another outbreak of corona viruses in the future. The genome of SARS-CoV-2 consists of around 30.000 RNA bases. Julia Weigand and team of scientists, which also includes scientists of the Goethe-University in Frankfurt (Prof. Dr. Maike Windbergs, Prof. Dr. Harald Schwalbe) are concentrating on the inhibition of the viral RNA. Together they combine expertise in structural research, medical chemistry, biology and pharmacy.
The aim of this project is to develop novel low molecular weight inhibitors targeting essential regulatory RNA elements in the genome of SARS-CoV-2. Based on preliminary work, with all NMR spectra of the 15 RNA regulatory elements assigned, NMR-based fragment screens against all 15 RNAs performed, and biological assays (including S3 conditions) established, the project team will first focus on targeting the RNA pseudoknot element that induces -1 ribosomal frameshifting to toggle between expression of ORF1a and ORF1b. The researchers identified three lead compounds that bind the pseudoknot and inhibited frameshifting with µM affinities and efficacies, and determined their binding epitope by NMR spectroscopy. This approach will be extended to target the attenuator sequence adjacent to the pseudoknot and also selected RNA elements from the 5′-untranslated region particularly involved in regulation of translation of viral proteins.