The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo–electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease 2019 (COVID-19), with over 84.66 million infections and 1.83 million deaths as reported on 3 January 2021 (refs. 1,2). SARS-CoV-2 is a positive-sense, single-stranded RNA virus. SARS-CoV-2 and several related beta-coronaviruses, including SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), are highly pathogenic. Infections can lead to severe acute respiratory syndrome, loss of lung function and, in severe cases, death. Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 has a higher capacity of human-to-human infections, which resulted in the rapidly growing pandemic 3. Finding an effective treatment for COVID-19, potentially also through drug repurposing, is an urgent but unmet medical need. Suramin (Fig. 1a) is a century-old drug that has been used to treat African sleeping sickness and river blindness 4,5. It has also been shown to be effective in inhibiting the replication of a wide range of viruses, including enteroviruses 6 , Zika virus 7 , Chikungunya 8 and Ebola viruses 9. The viral inhibition mechanisms of suramin are diverse, including inhibition of viral attachment, viral entry and release from host cells in part through interactions with viral capsid proteins 7,8,10,11. Recently, suramin has been shown to inhibit SARS-CoV-2 infection in cell culture by preventing cellular entry of the virus 12. Here we report that suramin is also a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), an essential enzyme for the viral life cycle. The potency of suramin in biochemical RdRp inhibition assays is at least 20-fold more potent than remdesivir, the current Food and Drug Administration-approved nucleotide drug for the treatment of COVID-19. The activity of suramin in cell-based viral inhibition is similar to remdesivir because the highly negative charge of suramin prevents efficient cellular uptake. A cryogenic electron microscopy (cryo-EM) structure reveals that suramin binds to the RdRp active site, blocking the binding of both RNA template and primer strands. These results provide a structural template for the design of next generation suramin derivatives as SARS-CoV-2 RdRp inhibitors. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin Wanchao Yin 1,