Abstract
Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, a well-known kinase inhibitor- Sorafenib showed a significant inhibition and dampened viral load in SARS-CoV-2 infected cells. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.
Highlights
RNA dependent RNA polymerases (RdRp) are conserved across all RNA virus superfamilies harbouring a positive or negative sense RNA genome with the exception of retroviruses
The on-going coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is significantly affecting the world health
Functional characterization of nucleotidyl transferase domain (NiRAN) domain from SARS-CoV-2 RdRp are provided in the S1 Data file
Summary
RNA dependent RNA polymerases (RdRp) are conserved across all RNA virus superfamilies harbouring a positive or negative sense RNA genome with the exception of retroviruses. The structure of RdRp is broadly divided into three domains- fingers, palm and thumb, the shape resembling that of a right hand. This structural organization is conserved in RNA viruses, and in the DNA polymerases across all kingdoms of life [1, 2]. The positive-stranded RNA (+RNA) viruses from the order Nidovirales present a conspicuous difference in the structural organization of their RdRp molecules [2,3,4]. Despite a significant difference in the sizes of their genomes which ranges from 13 kb to 35 kb, the RdRp molecules encoded by each genome show a common structural organization [2]
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