The SARS-CoV-2 Nsp3 Unique Domain (SUD) interacts with Guanine quadruplexes and this interaction is a potential antiviral target

ABSTRACT

The multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Previously, SARS-CoV Nsp3 has been shown to contain a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. In this presentation, we will show that the SARS-CoV-2 Nsp3 protein also contains a SUD domain interacting with G4s. We will present structural models for these interactions that reveal significant differences with the 3D structures of the SARS-CoV SUD/G4 complex. We will show data, obtained by three in vitro assays, characterizing the interactions between the SARSCoV- 2 SUD domain and different DNA and RNA G4s. Interestingly, these interactions can be disrupted by specific ligands of these G4s and some of these molecules can inhibit SARS-CoV-2 replication in human lung epithelial cell lines. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARSCoV- 2 replication and the use of inhibitors of these interactions as potent antiviral agents.