Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies

Ramaswamy, Kavitha; Rashid, Mariya; Selvarajan, R.; Jayavelu, Tamilselvan; Venkataraman, Sangita

doi:10.3390/v14102200

Cited by 8 publications

(9 citation statements)

References 100 publications

(171 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NSP12 of SARS-CoV-2 (PDB: 7BV2, [87]) consists of the interface domain (residues 251-365), the RdRp domain, and the N-terminal nidovirus RdRp-associated nucleotidyltransferase domain (NiRAN, residues 117-250) [88]. The core polymerase comprises the thumb subdomain, the palm subdomain, and the finger subdomain and is involved in the pivotal function of genome replication and transcription [89,90]. Earlier studies have indicated the role of various residues such as E254D, A423V, A656S, V720I, and V776L in NSP12, S25L and M75I, in NSP7 and the NSP8 mutation T145I in polymerization [91,92].…”

Section: Mutational Analysis Of Nsp 7-8-12mentioning

confidence: 99%

SARS-COV-2: Analysis of mutational impacts on non-structural proteins

Senthilazhagan

Sakthimani

Kallanja

et al. 2023

Preprint

View full text Add to dashboard Cite

The global pandemic that peaked in 2019 was caused by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus), which had China as its whenua. The whys and wherefores of this outbreak are attributed to the structural competency of the single-stranded RNA virus that continues to evolve posing major health concerns. SARS-CoV-2 with an increased level of genetic mutations alters the characteristics of the virus, such as transmissibility, and antigenicity alongside the development of drug and vaccine resistance. The deeper examination of prominent mutating sites and structures of the virus can give insights into the development of better and more efficient vaccine candidates. This research is steered to delve into the viral dynamics using full genome sequences and decode the genesis behind the structural and functional variances. The genomic data of SARS-CoV-2 variants were obtained from the Global Initiative on Sharing Avian Influenza Data (GISAID), and a set of significant mutations in each of the non-structural proteins (NSPs) 1 through 16 and structural proteins, including envelope, nucleocapsid, membrane, and spike, were identified. The mutations were characterized as stabilizing or destabilizing and their significance was analyzed with respect to self and in the context of interacting partners. Among all the proteins, NSP6 stands out as a dark horse with extremely high mutability. The results augment our understanding of how mutational events influence virus pathogenicity and evolution.

show abstract

Section: Mutational Analysis Of Nsp 7-8-12mentioning

confidence: 99%

SARS-COV-2: Analysis of mutational impacts on non-structural proteins

Senthilazhagan

Sakthimani

Kallanja

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…RdRp, a commonly conserved component of RNA viruses, is widely used as a target for antiviral drug screening [10]. Sofosbuvir is approved for the treatment of hepatitis important role in the replication and transcription of ZIKV and is absent in human beings, it has been proposed as a potential drug target for anti-ZIKV agents [9].…”

Section: Introductionmentioning

confidence: 99%

“…RdRp, a commonly conserved component of RNA viruses, is widely used as a target for antiviral drug screening [10]. Sofosbuvir is approved for the treatment of hepatitis C virus infection, primarily targeting RdRp.…”

Section: Introductionmentioning

confidence: 99%

Identification of Potent Zika Virus NS5 RNA-Dependent RNA Polymerase Inhibitors Combining Virtual Screening and Biological Assays

Chen

Chi

Zhang

et al. 2023

IJMS

View full text Add to dashboard Cite

The Zika virus (ZIKV) epidemic poses a significant threat to human health globally. Thus, there is an urgent need for developing effective anti-ZIKV agents. ZIKV non-structural protein 5 RNA-dependent RNA polymerase (RdRp), a viral enzyme for viral replication, has been considered an attractive drug target. In this work, we screened an anti-infection compound library and a natural product library by virtual screening to identify potential candidates targeting RdRp. Then, five selected candidates were further applied for RdRp enzymatic analysis, cytotoxicity, and binding examination by SPR. Finally, posaconazole (POS) was confirmed to effectively inhibit both RdRp activity with an IC50 of 4.29 μM and the ZIKV replication with an EC50 of 0.59 μM. Moreover, POS was shown to reduce RdRp activity by binding with the key amino acid D666 through molecular docking and site-directed mutation analysis. For the first time, our work found that POS could inhibit ZIKV replication with a stronger inhibitory activity than chloroquine. This work also demonstrated fast anti-ZIKV screening for inhibitors of RdRp and provided POS as a potential anti-ZIKV agent.

show abstract

“…RdRps' right hand is closed and they share a common core architecture with 7 highly conserved motifs named A to G (2,3). The detailed structure of RdRps has been largely discussed elsewhere (2,(4)(5)(6) and the structural overview presented here only provides the minimal background to discuss the impact of phosphorylation sites.…”

Section: Introductionmentioning

confidence: 99%

Regulation of viral RNA-dependent RNA polymerases by phosphorylation

Duflos

Michiels

2023

Front. Virol.

View full text Add to dashboard Cite

RNA viruses encode an RNA-dependent RNA polymerase (RdRp), which is essential for transcription and replication of their genome since host cells lack equivalent enzymes. RdRp residues were shown to be phosphorylated by host kinases in several human, animal or plant viruses including flaviviruses, picornaviruses, coronaviruses, influenza viruses and tymoviruses. RdRps can be phosphorylated on several residues by distinct host kinases. Phosphomimetic mutations of identified phosphorylated residues either positively or negatively regulate RNA synthesis or association of RdRps with RNA or other proteins. Interestingly, some RdRps evolved to recruit cellular kinases through direct protein-protein interaction, likely to promote or to tightly control their own phosphorylation. Given the essential nature of RdRps for RNA virus replication, a better knowledge of RdRps’ phosphorylation is expected to facilitate the design of future drugs that strongly affect polymerase activity.

show abstract

Revisiting Viral RNA-Dependent RNA Polymerases: Insights from Recent Structural Studies

Cited by 8 publications

References 100 publications

SARS-COV-2: Analysis of mutational impacts on non-structural proteins

SARS-COV-2: Analysis of mutational impacts on non-structural proteins

Identification of Potent Zika Virus NS5 RNA-Dependent RNA Polymerase Inhibitors Combining Virtual Screening and Biological Assays

Regulation of viral RNA-dependent RNA polymerases by phosphorylation

Contact Info

Product

Resources

About