Mechanisms of inhibition of viral RNA replication by nucleotide analogs

Johnson, Kenneth A.; Dangerfield, Tyler L.

doi:10.1016/bs.enz.2021.07.001

Cited by 15 publications

(18 citation statements)

References 49 publications

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“…Nucleotide addition cycle (NAC), a process shared by all nucleic acid polymerases carrying out NTP/dNTP-driven phosphodiester bond formation ( Huang et al, 1998 ; Li et al, 1998 ; Yin and Steitz, 2004 ; Kornberg, 2007 ; Gong and Peersen, 2010 ), may thus be the most conservative part of viral RdRP working mechanisms. Understandings of common features in RdRP NAC can help describe the viral genome replication and transcription processes that are composed of thousands of NACs and can benefit development of nucleot(s)ide analog drugs targeting viral RdRPs ( Gong, 2021 ; Johnson and Dangerfield, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Within and Beyond the Nucleotide Addition Cycle of Viral RNA-dependent RNA Polymerases

Gong

2022

Front. Mol. Biosci.

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Nucleotide addition cycle (NAC) is a fundamental process utilized by nucleic acid polymerases when carrying out nucleic acid biosynthesis. An induced-fit mechanism is usually taken by these polymerases upon NTP/dNTP substrate binding, leading to active site closure and formation of a phosphodiester bond. In viral RNA-dependent RNA polymerases, the post-chemistry translocation is stringently controlled by a structurally conserved motif, resulting in asymmetric movement of the template-product duplex. This perspective focuses on viral RdRP NAC and related mechanisms that have not been structurally clarified to date. Firstly, RdRP movement along the template strand in the absence of catalytic events may be relevant to catalytic complex dissociation or proofreading. Secondly, pyrophosphate or non-cognate NTP-mediated cleavage of the product strand 3′-nucleotide can also play a role in reactivating paused or arrested catalytic complexes. Furthermore, non-cognate NTP substrates, including NTP analog inhibitors, can not only alter NAC when being misincorporated, but also impact on subsequent NACs. Complications and challenges related to these topics are also discussed.

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Section: Introductionmentioning

confidence: 99%

Within and Beyond the Nucleotide Addition Cycle of Viral RNA-dependent RNA Polymerases

Gong

2022

Front. Mol. Biosci.

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“…14−18 Since the outbreak of the pandemic, nucleotide analogues have been widely explored as potential inhibitors to terminate the RNA synthesis in SARS-CoV-2 RdRp. 5,7,8,[10][11][12]19 Remdesivir is one representative prodrug of a nucleotide analogue that has demonstrated therapeutic efficacy in the animal model of SARS-CoV-2 RdRp 20 and effectively terminated viral RNA synthesis in biochemical experiments through a "delayed termination mechanism". 17,18,21−26 The chemical structure of remdesivir's active form (RDV-TP) resembles that of natural adenosine triphosphate (ATP) (Figure 1B,C).…”

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“…The outbreak of coronavirus disease 2019 (COVID-19) has become a global pandemic, and over 542 million confirmed cases have been reported by June 2022 . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus that has caused COVID-19 and can be furtively transmitted among humans. , To curb the health crisis, great efforts have been devoted to exploring the effective treatment for COVID-19. − …”

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“…It is the minimal scaffold to mediate the RNA synthesis and plays a central role in viral replication and transcription. It is composed of three nonstructural proteins (nsps) (Figure A), where nsp12 mainly conducts the RNA synthesis in the active site, while nsp7 and nsp8 serve as cofactors to stimulate RNA-dependent RNA polymerase (RdRp) activity. − Since the outbreak of the pandemic, nucleotide analogues have been widely explored as potential inhibitors to terminate the RNA synthesis in SARS-CoV-2 RdRp. ,,,− , …”

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Unveiling the “Template-Dependent” Inhibition on the Viral Transcription of SARS-CoV-2

Luo

Wang

Yao

et al. 2022

J. Phys. Chem. Lett.

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Remdesivir is one nucleotide analogue prodrug capable to terminate RNA synthesis in SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) by two distinct mechanisms. Although the “delayed chain termination” mechanism has been extensively investigated, the “template-dependent” inhibitory mechanism remains elusive. In this study, we have demonstrated that remdesivir embedded in the template strand seldom directly disrupted the complementary NTP incorporation at the active site. Instead, the translocation of remdesivir from the +2 to the +1 site was hindered due to the steric clash with V557. Moreover, we have elucidated the molecular mechanism characterizing the drug resistance upon V557L mutation. Overall, our studies have provided valuable insight into the “template-dependent” inhibitory mechanism exerted by remdesivir on SARS-CoV-2 RdRp and paved venues for an alternative antiviral strategy for the COVID-19 pandemic. As the “template-dependent” inhibition occurs across diverse viral RdRps, our findings may also shed light on a common acting mechanism of inhibitors.

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“…1A), where nsp12 mainly conducts the RNA synthesis in the active site, and nsp7 and nsp8 serve as cofactors to stimulate RNA-dependent RNA polymerase (RdRp) activity [6][7][8][9][10] . Since the outbreak of the pandemic, nucleotide analogs have been widely explored as potential inhibitors to terminate the RNA synthesis in SARS-CoV-2 RdRp 5,[11][12][13][14][15] .…”

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confidence: 99%

1’-cyano substitution of Remdesivir “template-dependent” inhibiting the transcription of SARS-CoV-2

Luo

Wang

Gao

et al. 2022

Preprint

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Remdesivir is one nucleotide analog prodrug capable to terminate RNA synthesis in SARS-CoV-2 RdRp by two distinct mechanisms. The “delayed chain termination mechanism” has been extensively investigated, while the “template-dependent inhibition mechanism” remains elusive. In this study, we have demonstrated that Remdesivir embedded in the template strand seldom directly disrupted the complementary NTP incorporation at the active site. Instead, the translocation of the template strand from +2 to +1 site was hindered, as the 1’-cyano group of Remdesivir would sterically clash with V557. Moreover, we have elucidated the molecular mechanism of how SARS-CoV-2 RdRp gained the drug resistance to Remdesivir upon V557L mutation. Overall, our studies provided valuable insight into the “template-dependent inhibition mechanism” exerted by Remdesivir on SARS-CoV-2 RdRp and paved venues for an alternative drug design strategy for the treatment of COVID-19.

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Mechanisms of inhibition of viral RNA replication by nucleotide analogs

Cited by 15 publications

References 49 publications

Within and Beyond the Nucleotide Addition Cycle of Viral RNA-dependent RNA Polymerases

Within and Beyond the Nucleotide Addition Cycle of Viral RNA-dependent RNA Polymerases

Unveiling the “Template-Dependent” Inhibition on the Viral Transcription of SARS-CoV-2

1’-cyano substitution of Remdesivir “template-dependent” inhibiting the transcription of SARS-CoV-2

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