Identification and characterization of mutations in the SARS-CoV-2 RNA-dependent RNA polymerase as a promising antiviral therapeutic target

Abstract

The causative agent of COVID-19 is a novel betacoronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV-2), which has emerged as a pandemic of global concern. Considering its rapid transmission, WHO has declared public health emergency on 11th March 2020 worldwide. SARS-CoV-2 is a genetically diverse positive sense RNA virus that typically exhibit high rates of mutation than DNA viruses. Higher rates of mutation bring higher genomic variability which may lead to viral evolution and enabling viruses to evade the pre-existing immunity of host and quickly acquire drug resistance properties. The objective of our study was to compare the SARS-CoV-2 RdRp sequences of Indian SARS-CoV-2 isolates with those of Wuhan type virus. A total of 384 point mutations were detected from 488 sequence of the RdRp protein of Indian SARS-CoV-2 genome, out of which seven were used for subsequent study. Furthermore, prediction of secondary structure, protein modeling and its dynamics were performed which revealed that seven mutations (R118C, T148I, Y149C, E802A, Q822H, V880I and D893Y) significantly altered the stability and flexibility of RdRp protein. Present study was therefore, undertaken to analyze the variations occurring in RdRp due to multiple mutations leading to the alterations in the structure and function of RNA-dependent RNA polymerase which is essential for the replication /transcription of this virus and hence can be utilized as a promising therapeutic target to curb SARS-CoV-2 infections. Supplementary Information The online version contains supplementary material available at 10.1007/s00203-021-02527-9.

Molecular and Structural Analysis of Specific Mutations from Saudi Isolates of SARS-CoV-2 RNA-Dependent RNA Polymerase and their Implications on Protein Structure and Drug–Protein Binding

“…In this study, we evaluated several mutations of the RdRp enzyme extracted from Saudi Arabia SARS-CoV-2 isolates and aligned them with the Wuhan RdRp enzyme to highlight key mutations that effect the enzyme structure, function and dynamics and overall virus pathogenicity, transmissibility and disease mortality. The findings of this study were found to be consistent with those of Pachetti et al [ 5 ] and Yashvardhini et al [ 27 ], who described the RdRp of SARS-CoV-2 acquiring drug-resistance properties due to the occurrence of a high frequency of mutations in the RdRp of infected populations worldwide and in India, respectively. The findings will not only give key findings to the society of the virus pathogenic strains circulating in Saudi Arabia but also will guide the discovery of novel drugs.…”

Theoretical insights into the effect of halogenated substituent on the electronic structure and spectroscopic properties of the favipiravir tautomeric forms and its implications for the treatment of COVID-19

“…According to Yashvardhini et al , the mutation in which tyrosine is replaced by cysteine (Indian variant) increased the structural flexibility of the enzyme and hence can influence the viral replication. 70 Note that the docking results for this mutant are shown in Table 5 . By observing these results, we can notice that the compounds have a nice affinity in the mutant RdRp active site, with energy values ranging from of −5.4 to −5.6 kcal mol −1 , respectively.…”

Prediction of binding of FDA approved drug Ledipasvir to SARS-CoV2 mutants: an in silico study

“…Recently, ledipasvir, another nucleoside analog, has been approved for the treatment of SARS-CoV2 infection. Furthermore, certain mutations in RdRp are reported to cause resistance to remdesivir (5). Therefore, focused research studies are required to characterize mutations to understand the effect on drug resistance.…”

“…Newer drugs, including ledipasvir, have been sanctioned for the treatment of SARS-CoV2 infection (4). The continuous emergence of variants throughout the globe highlights the importance to characterize replication related mutations in order to understand drug resistance (5). Furthermore, the correlation of mutations with diseases severity needs to be assessed.…”