Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting

Robson, Fran; Khan, Khadija; Le, Thi Khanh; Paris, Clément; Demirbag, Sinem; Barfuss, Peter; Rocchi, Palma; Ng, W. F.

doi:10.1016/j.molcel.2020.11.048

Cited by 130 publications

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“…In contrast to all other known RNA viruses, coronaviruses do not mutate as much. They have a correction system for genome replication, a proofreading enzyme, which removes mismatched nucleotides during replication and transcription [ 1 , 2 ]. The non-structural protein nsp14 encodes an exonuclease which is essential for replication fidelity.…”

Section: Introductionmentioning

confidence: 99%

“…The non-structural protein nsp14 encodes an exonuclease which is essential for replication fidelity. If it is deleted, the mutation rates increase 15- to 20-fold, which can become lethal for the virus of this large size [ 2 , 3 ]. This is a consequence of the rather large genome size of the coronaviruses, which is about 30,000 bases long, about 3-fold the size of influenza or HIV RNAs.…”

Section: Introductionmentioning

confidence: 99%

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Within-Host and Between-Host Evolution in SARS-CoV-2—New Variant’s Source

Moelling

2021

Viruses

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Some of the newly emerging corona viral variants show high numbers of mutations. This is unexpected for a virus with a low mutation rate due to an inherent proof-reading system. Could such a variant arise under very special conditions occurring in a host where the virus replicates and mutates in a rather unlimited fashion, such as in immune compromised patients? The virus was shown to replicate in an immunosuppressed cancer patient for more than 105 days and might be a source of new variants. These patients are asymptomatic and the virus may therefore escape detection and attention and be high-risk. Similarly, HIV-infected individuals may be immunocompromised and support coronavirus replication with increased mutation rates. The patients may promote “within-host evolution”. Some of the viruses present in such a highly mutagenic swarm or quasispecies within one patient may become founders and cause a pandemic by further “between-host evolution”. B.1.1.7 with 23 mutations may be such a case. Immunosuppressed patients can be identified and treated by the synthetic antibody cocktails as passive immunization and kept under control. Immunosuppressed patients can be easily identified and supervised by healthcare workers—once they become aware of the risk—to avoid new variants with pandemic potential.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Within-Host and Between-Host Evolution in SARS-CoV-2—New Variant’s Source

Moelling

2021

Viruses

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“…The SARS-CoV-2 replication transcription complex (RTC) is composed of nsp7/8/12 and several other non-structural proteins involved in activities that include RNA capping, RNA unwinding and proofreading [ 38 ]. Nsp14 contains the ExoN activity that can reduce susceptibility to nucleotide analogue inhibitors [ 39 ].…”

Section: Future Directionsmentioning

confidence: 99%

Remdesivir for the treatment of Covid-19: the value of biochemical studies

Götte

2021

Current Opinion in Virology

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The nucleotide analogue prodrug remdesivir remains the only FDA-approved antiviral small molecule for the treatment of infection with SARS-CoV-2. Biochemical studies revealed that the active form of the drug targets the viral RNA-dependent RNA polymerase and causes delayed chain-termination. Delayed chain-termination is incomplete, but the continuation of RNA synthesis enables a partial escape from viral proofreading. Remdesivir becomes embedded in the copy of the RNA genome that later serves as a template. Incorporation of an incoming nucleotide triphosphate is now inhibited by the modified template. Knowledge on the mechanism of action matters. Enzymatic inhibition links to antiviral effects in cell cultures, animal models and viral load reduction in patients, which provides the logical chain that is expected for a direct acting antiviral. Hence, remdesivir also serves as a benchmark in current drug development efforts that will hopefully lead to orally available treatments to the benefit of a broader population.

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“…Single‐stranded RNA genome of severe acute respiratory syndrome coronavirus 2. Two‐thirds of the genome encodes two major polyproteins, pp1a and pp1ab, which are divided into 16 nonstructural proteins 40 …”

Section: Introductionmentioning

confidence: 99%

Coronavirus genomic nsp14‐ExoN, structure, role, mechanism, and potential application as a drug target

Tahir

2021

Journal of Medical Virology

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The recent coronavirus disease 2019 , causing a global pandemic with devastating effects on healthcare and social-economic systems, has no special antiviral therapies available for human coronaviruses (CoVs). The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) possesses a nonstructural protein (nsp14), with amino-terminal domain coding for proofreading exoribonuclease (ExoN) that is required for high-fidelity replication. The ability of CoVs during genome replication and transcription to proofread and exclude mismatched nucleotides has long hindered the development of anti-CoV drugs. The resistance of SARS-CoV-2 to antivirals, especially nucleoside analogs (NAs), shows the need to identify new CoV inhibition targets.Therefore, this review highlights the importance of nsp14-ExoN as a target for inhibition. Also, nucleoside analogs could be used in combination with existing anti-CoV therapeutics to target the proofreading mechanism.

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Coronavirus RNA Proofreading: Molecular Basis and Therapeutic Targeting

Cited by 130 publications

References 0 publications

Within-Host and Between-Host Evolution in SARS-CoV-2—New Variant’s Source

Within-Host and Between-Host Evolution in SARS-CoV-2—New Variant’s Source

Remdesivir for the treatment of Covid-19: the value of biochemical studies

Coronavirus genomic nsp14‐ExoN, structure, role, mechanism, and potential application as a drug target

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