Targeting the RNA-dependent RNA Polymerase (RdRp) Complex of SARS CoV-2 for the discovery of antiviral molecules

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is a positive sense, single stranded RNA virus belonging to the Coronaviridae family within the Nidovirales order. It is highly transmissible and pathogenic coronavirus that emerged in late 2019 and is responsible for the ongoing pandemic of severe acute respiratory disease – (COVID-19). Until now, it has affected more than 178 million individuals globally and claimed ~3.8 million lives, thus threatening human health and livelihood. The SARS CoV-2 genome is very large (~30kb) and codes for 16 non-structural proteins (nsps), 4 structural proteins (Spike (S), Membrane (M), Nucleoprotein (N) and Envelope (E)) and 9 accessory proteins. The interactions between these proteins help in successful infection of host, replication of viral genome, assembly & packaging to form viral progeny and aid the survival of the virus. The RNA-dependent-RNA-Polymerase (RdRp) complex of SARS CoV-2 is responsible for replication and transcription of the viral genome. nsp12 is the main catalytic subunit within the RdRp complex while interacts with its cofactors nsp7 and nsp8 (the primase complex; primarily in hetero-tetrameric configuration) and RNA-binding nsp9, to achieve maximum processivity for RNA replication & transcription. Targeting relevant protein-protein interaction interfaces (PPIIs) is a viable paradigm for designing antiviral drugs. The amino acid hot-spots in these PPIIs are prime targets for small-molecule via Orthosteric PPII disruptors which act directly on the PPII or by Allosteric means where the small molecule bind to sites that are topologically distinct from PPIIs and affect the PPIIs distantly. The current study aims to target the Protein-Protein Interaction Interfaces (PPIIs) between the members of the Rdrp Complex (nsp7-nsp8; nsp7-nsp8-nsp12; nsp8-nsp12; nsp7-nsp12; nsp9 nsp12) to discover antiviral molecules.