Studying SARS-CoV-2 Protein-RNA Complexes

The way in which proteins and RNA interact in coronaviruses is so far mostly unknown, although a better understanding of these interactions will open up opportunities for therapeutic interventions. In recent years, our groups have jointly developed an innovative approach to study protein-RNA interactions that is fast and sensitive. In this project we will apply this method to SARS-CoV-2 and use the data to direct drug discovery. Part of the work will be carried out in collaboration with the international consortium COVID19-NMR (covid19-nmr.de).

Initially, we will use structural biology methods to study protein-RNA interactions between two important viral proteins and their interacting RNAs. Using different experimental and computational methods, we will precisely locate binding sites in these protein-RNA complexes. In a second step, these regions of interaction will allow us to search for compounds that specifically interfere with the binding.

Initial work will focus on the nucleocapsid N protein and the non-structural CoV protein, Nsp3. We will combine the techniques of Nuclear Magnetic Resonance (NMR) spectroscopy and cross-linking with ultraviolet light coupled to mass spectrometry (XL-MS) to obtain information about protein-RNA interaction sites on the target proteins faster than by conventional methods. Structures of the entire protein-RNA complexes can also be obtained in this way. In the second stage of the project, the “druggability” of the interaction sites will be investigated by testing a library of drug compounds to see whether they can interfere with the protein-RNA interactions.

The development of effective vaccines and of drugs to treat COVID-19 is a key response to the pandemic. Although current advances in vaccine development are promising, it is not yet clear how long immunity will last and whether mutations in the virus will affect vaccine efficiency. Our contribution to drug development focuses on a specific type of biomolecule interaction and differs from the more generic strategies that are commonly used. In addition, we will generate structural information that will be important for understanding basic aspects of SARS-CoV-2 biology.

Rapid Hybrid Structure Determination of Coronavirus Protein-RNA Complexes as a Basis for Drug Screening for the Treatment of COVID-19