Incorporation efficiency and inhibition mechanism of 2′-substituted nucleotide analogs against SARS-CoV-2 RNA-dependent RNA polymerase

Yuan, Congmin; Goonetilleke, Eshani Chrisana; Unarta, Ilona Christy; Huang, Xuhui

doi:10.1039/d1cp03049c

Cited by 12 publications

(18 citation statements)

References 59 publications

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“… 33 , 34 , 47 They can immediately inhibit the next nucleotide addition once it is incorporated into the nascent strand, and previous work has shown the steric effect caused by the 2′-methyl group substitution could facilitate the immediate termination on SARS-CoV-2 RdRp. 48 The above examples have demonstrated that nucleotide analogues with modification on the ribose could serve as promising inhibitors to terminate the nucleotide addition in SARS-CoV-2 RdRp.…”

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confidence: 99%

2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2

Zhang

Gao

et al. 2022

J. Phys. Chem. Lett.

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Inhibition of RNA-dependent RNA polymerase (RdRp) by nucleotide analogues with ribose modification provides a promising antiviral strategy for the treatment of SARS-CoV-2. Previous works have shown that remdesivir carrying 1′-substitution can act as a “delayed chain terminator”, while nucleotide analogues with 2′-methyl group substitution could immediately terminate the chain extension. However, how the inhibition can be established by the 3′-ribose modification as well as other 2′-ribose modifications is not fully understood. Herein, we have evaluated the potential of several adenosine analogues with 2′- and/or 3′-modifications as obligate chain terminators by comprehensive structural analysis based on extensive molecular dynamics simulations. Our results suggest that 2′-modification couples with the protein environment to affect the structural stability, while 3′-hydrogen substitution inherently exerts “immediate termination” without compromising the structural stability in the active site. Our study provides an alternative promising modification scheme to orientate the further optimization of obligate terminators for SARS-CoV-2 RdRp.

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confidence: 99%

2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2

Zhang

Gao

et al. 2022

J. Phys. Chem. Lett.

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“…Similarly, mechanistic studies are lacking for SARS-CoV-2 RdRp inhibition by AT-527 ( 16 ), whose base is converted into guanine in vivo to form the active triphosphate metabolite AT-9010 [ 102 ]. However, it should be noted that the uridine analog of AT-9010, sofosbuvir, induces immediate chain termination after incorporation into RNA by SARS-CoV-2 RdRp, likely mediated by strong steric hindrance introduced by its bulky 2′-methyl group [ 103 , 104 ]. The mechanism of action for molnupiravir ( 17 ) is complex and distinct from chain-terminating nucleotides.…”

Section: Rna-dependent Rna Polymerase (Rdrp)mentioning

confidence: 99%

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

Correia

Seagal

et al. 2022

Viruses

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The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.

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“…Molecular dynamics (MD) simulation has become a useful tool to resolve the dynamics of biological macromolecules at the atomic resolution. Recently, it has been widely utilized for drug screening and examining the mechanisms of nucleotide analogs on the nucleotide addition in SARS-CoV-2 RdRp 4,5,8,[23][24][25][26][27][28] . However, the timescale for one turnover of nucleotide addition cycle has been estimated at several milliseconds for viral RdRps 29,30 , which is difficult to be directly accessed by conventional MD simulations usually covering the timescales up to hundreds of nanoseconds or a few microseconds for the biological macromolecules.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 RdRp Follows Asynchronous Translocation Pathway for Viral Transcription and Replication

Wang

Yao

Gao

et al. 2022

Preprint

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RNA-dependent RNA polymerase (RdRp) is the replicase machinery for SARS-CoV-2 and thereby it has become one of the most promising drug targets to combat the pandemic as well as the healthy threat posed by the novel coronavirus. Translocation is one essential step for RdRp to exert the viral replication and transcription, and it describes the dynamic process in which the double-stranded RNA moves upstream by one base pair position to empty the active site for the continuous substrate incorporation. However, the molecular mechanisms underlying the dynamic translocation of SARS-CoV-2 RdRp remain elusive. In the current study, we have elucidated the molecular insights into the translocation dynamics of SARS- CoV-2 RdRp by constructing a Markov State Model based on extensive molecular dynamics simulations. We have identified two previously uncharacterized intermediates which pinpoint an asynchronous and rate-limiting translocation of the nascent-template duplex. The movement of the 3’-terminal nucleotide in the nascent strand lags behind its upstream nucleotides due to the uneven protein environment while the translocation of template strand is delayed by the hurdle residue K500. Although the motions of the two strands are not synchronous, they share the same “ratchet” to stabilize the system in the post-translocation state, suggesting a coupled Brownian-ratchet model. Overall, our study has provided the intriguing insights into the translocation dynamics with unprecedented molecular details, which would significantly deepen our understanding about the transcriptional mechanisms of SARS-CoV-2.

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Incorporation efficiency and inhibition mechanism of 2′-substituted nucleotide analogs against SARS-CoV-2 RNA-dependent RNA polymerase

Abstract: The ongoing pandemic caused by SARS-CoV-2 emphasizes the need for effective therapeutics. Inhibition of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) by nucleotide analogs provides a promising antiviral strategy. One common group...

Cited by 12 publications

References 59 publications

2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2

2′- and 3′-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

SARS-CoV-2 RdRp Follows Asynchronous Translocation Pathway for Viral Transcription and Replication

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