Unveiling SARS-CoV-2's heart: role, structure and inhibition of SARS-CoV-2 RNA-dependent RNA polymerase

SARS-CoV-2 emergence in late 2019 represented an incredible challenge for virological research and the development of novel as well as repurposed antiviral agents. Among the targeted viral proteins, one is nsp12 that carries the RNA-dependent RNA polymerase (RdRp) activity, essential for the viral replication. Together with nsp7 and nsp8 cofactors, having an essential role in aiding processivity and associated with several other nonstructural proteins such as helicase, methyltransferase, endo- and exonuclease, nsp12 forms the large viral replication and transcription complex (RTC). Within such RTC, nsp12 catalyzes the synthesis of one of the longest RNA genomes in the viral world, requiring exceptional speed, processivity and fidelity compared to other viral RdRps. Moreover, the peculiar replication cycle of coronaviruses requires nsp12 to perform less conventional functions in backtracking on the viral genome for proof-reading activity and “jumping” during discontinuous synthesis of subgenomic mRNAs. The structure of the minimal RTC was resolved with a resolution <3 Å by cryo-electron microscopy in complex with RNA and with inhibitors, opening the doors to structural studies on its functions and drug development. Given its essential role in viral replication, extensive research was carried out over the last years to identify both nucleoside (NI) and non-nucleoside (NNI) inhibitors, resulting in two NIs reaching clinical use, although their efficacy in vivo is still under evaluation. This review aims at summarizing the currently known structural and functional aspects and the state-of-the art in drug discovery for SARS-CoV-2 RdRp.