Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2

Abstract

The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate–binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.

Communicated by Ramaswamy H. Sarma

AEGIS nucleotides can act as potent inhibitors of the RdRp by denying the access of the viral RNA to the replicative polymerase.

Keywords:

• SARS-CoV-2
• RdRp
• AEGIS
• antiviral agents
• COVID-19

Acknowledgements

SP is thankful to the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India for providing a research fellowship. We also thank IIITDMJ, NIPER-K, and NIPER-G for various facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

NRJ and HKS thank the Science and Engineering Research Board (SERB), Department of Science and Technology (DST, New Delhi) for the financial supports.