Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

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 th...

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Bibliographic Details
Published in:PLoS computational biology 2021-09, Vol.17 (9), p.e1009384-e1009384
Main Authors: Dwivedy, Abhisek, Mariadasse, Richard, Ahmad, Mohammed, Chakraborty, Sayan, Kar, Deepsikha, Tiwari, Satish, Bhattacharyya, Sankar, Sonar, Sudipta, Mani, Shailendra, Tailor, Prafullakumar, Majumdar, Tanmay, Jeyakanthan, Jeyaraman, Biswal, Bichitra Kumar
Format: Article
Language:English
Subjects:
Antiinfectives and antibacterials
Antiviral agents
Biology and life sciences
Coronaviruses
COVID-19
DNA-directed RNA polymerase
Domains
Enzyme inhibitors
Genomes
Health aspects
Infectivity
Kinases
Lead compounds
Medicine and health sciences
Microorganisms
Molecular docking
Nucleoside triphosphates
Pandemics
Phosphotransferase
Polypeptides
Protein binding
Proteins
Research and Analysis Methods
RNA polymerase
RNA polymerases
RNA-directed RNA polymerase
Severe acute respiratory syndrome
Severe acute respiratory syndrome coronavirus 2
Structure
Therapeutic targets
Viral diseases
Viral proteins
Virus research
Viruses
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Summary: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.
ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1009384