Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin

Abstract

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,

Electron Density Analysis of SARS-CoV-2 RNA-Dependent RNA Polymerase Complexes

“…The complexes were not changed and were taken for computations as they are. RdRp complexes with favipiravir-RTP (7AAP und 7CTT) and with suramin (7D4F) [ 28 ] were selected and analyzed ( Figure 1 ). In 7AAP and 7CTT complexes, the favipiravir-RTP ligand has different conformations.…”

Recent advances in developing small-molecule inhibitors against SARS-CoV-2

“…Unlike earlier expectations, remdesivir appeared to have little, or no, effect on hospitalized COVID-19 patients in terms of overall mortality, initiation of ventilation and duration of hospital stay 124 , 125 . Yin et al 126 have reported that suramin, a 100-year-old drug, and its derivatives are at least 20-fold more potent than remdesivir in inhibiting SARS-CoV-2 infection by targeting RdRp. The crystal structure of RdRp in complex with suramin has revealed two binding sites in RdRp ( Fig.…”

“…5 C). As a non-nucleotide inhibitor, suramin could ultimately aid in structure-based drug development for COVID-19 126 .…”

SARS-CoV-2 subgenomic RNA kinetics in longitudinal clinical samples

“…Additionally, in order to serve as a marker of replicating virus, sgRNA is expected to show a rapid decline after transcriptional inhibition due to ribonuclease degradation, in contrast to gRNA, which may be protected from degradation by viral capsids and therefore persist more durably (16). Therefore, we hypothesized that, upon treatment with SARS-CoV-2 RNA-dependent RNA polymerase inhibitors (17, 18, 19) in cell lines infected with SARS-CoV-2, we should observe a rapid decline of sgRNA after viral death when compared with gRNA.…”