tetano
Editor, Senior Moderator
PLoS Comput Biol
. 2021 Sep 13;17(9):e1009384.
doi: 10.1371/journal.pcbi.1009384. Online ahead of print.
Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2
Abhisek Dwivedy[SUP] 1 [/SUP], Richard Mariadasse[SUP] 2 [/SUP], Mohammed Ahmad[SUP] 1 [/SUP], Sayan Chakraborty[SUP] 1 [/SUP], Deepsikha Kar[SUP] 1 [/SUP], Satish Tiwari[SUP] 1 [/SUP], Sankar Bhattacharyya[SUP] 3 [/SUP], Sudipta Sonar[SUP] 3 [/SUP], Shailendra Mani[SUP] 3 [/SUP], Prafullakumar Tailor[SUP] 1 [/SUP], Tanmay Majumdar[SUP] 1 [/SUP], Jeyaraman Jeyakanthan[SUP] 2 [/SUP], Bichitra Kumar Biswal[SUP] 1 [/SUP]
Affiliations
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.
. 2021 Sep 13;17(9):e1009384.
doi: 10.1371/journal.pcbi.1009384. Online ahead of print.
Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2
Abhisek Dwivedy[SUP] 1 [/SUP], Richard Mariadasse[SUP] 2 [/SUP], Mohammed Ahmad[SUP] 1 [/SUP], Sayan Chakraborty[SUP] 1 [/SUP], Deepsikha Kar[SUP] 1 [/SUP], Satish Tiwari[SUP] 1 [/SUP], Sankar Bhattacharyya[SUP] 3 [/SUP], Sudipta Sonar[SUP] 3 [/SUP], Shailendra Mani[SUP] 3 [/SUP], Prafullakumar Tailor[SUP] 1 [/SUP], Tanmay Majumdar[SUP] 1 [/SUP], Jeyaraman Jeyakanthan[SUP] 2 [/SUP], Bichitra Kumar Biswal[SUP] 1 [/SUP]
Affiliations
- PMID: 34516563
- DOI: 10.1371/journal.pcbi.1009384
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.