Investigating drug susceptibility to SARS-CoV-2 nuclear capsid protein interactions

The groups of Alllain (IBC), Gossert (BNSP), and Leitner (IMSB) investigated the susceptibility of RNA interactions to the nucleocapsid protein of SARS-CoV-2 with a hybrid structure determination approach, which led to preliminary part results. Their findings have been published in Nucleic acid research.

Along with effective vaccines, antiviral compounds represent an essential approach to combating viral diseases. The D-BIOL groups led by Frédéric Allen, Alvar Gossert and Alexander Leitner investigated whether interactions between the SARS-CoV-2 nucleocapsid protein, which possesses two known RNA-binding domains, and sm2 RNA located in the 3’UTR of the SARS-CoV-2 nucleocapsid could be The cov-2 RNA is drug-worthy.

They chose a hybrid structural approach based on solution NMR and cross-linking MS experiments to rapidly obtain structural information on these complexes. This information was then used to generate constraints for building models of sm2-RNA complexes and the two RNA-binding domains of the nuclear capsid protein, for which previously unlinked structures were resolved. This approach resulted in the first model of how one RNA-binding domain interacts with RNA and expanded knowledge of the other RNA-binding domain.

An NMR-based fragment screen was then used to identify compounds bound to either protein or RNA domains in isolation. From these compounds, compounds that bind to the interaction interface of the respective molecules, which were known from hybrid structural approach models, were selected. Overall, the experiments revealed that these RNA–protein interactions appear to be treatable. Therefore, the identified compounds provide the basis for developing more effective molecules that block protein-RNA interactions.