Antiviral Activity of Nucleoside Analogues against SARS-coronavirus (SARS-CoV)

Chu, Chung K.; Gadthula, Srinivas; Chen, Xin; Choo, Hyunah; Ölgen, Süreyya; Barnard, Dale L.; Sidwell, Robert W.

doi:10.1177/095632020601700506

Cited by 49 publications

(48 citation statements)

References 22 publications

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“…However, identification and development of antiviral nucleosides against coronaviruses have been hampered by the presence of the unique CoV proofreading 3′-5′ exoribonuclease (ExoN) ( 16 – 18 ). While nucleoside analogues such as BCX4430 inhibit CoVs ( 19 ), several previously tested nucleoside analogues have been incapable of potently inhibiting CoV replication, and others have demonstrated poor selectivity indexes ( 20 , 21 ). We have shown that CoV resistance to the mutagens 5-fluorouracil (5-FU) and ribavirin (RBV) in vitro is attributed to their removal by the proofreading ExoN ( 22 ), supporting the hypothesis that an effective nucleoside analogue must evade proofreading to successfully interfere with CoV RNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Agostini

Andres

Sims

et al. 2018

mBio

1,286

1,501

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Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs in vitro and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC50) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC50. The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS-CoV resulted in the same in vitro resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.

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Section: Introductionmentioning

confidence: 99%

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Agostini

Andres

Sims

et al. 2018

mBio

1,286

1,501

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“…It serves as a more preferential substrate for the HSV-encoded thymidine-kinase than host cell kinases for its initial phosphorylation (Frobert et al , 2005; Jiao et al , 2019). Previously, 3′-azido-2′,3′-unsaturated thymine analogue has shown better activity compared to other nucleoside analogues against SARS-CoV (EC50=10.3 µM) with a significant level of toxicity (Chu et al , 2006). These findings will be helpful towards developing new antiviral candidates for SARS-CoV-2 where uracil/thymidine analogues may have an upper hand.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 has observably higher propensity to accept uracil as nucleotide substitution: Prevalence of amino acid substitutions and their predicted functional implications in circulating SARS-CoV-2 in India up to July, 2020

Roy

Nath

Mallick

et al. 2020

Preprint

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SARS-CoV-2 has emerged as pandemic all over the world since late 2019. In this study, we investigated the diversity of the virus in the context of SARS-CoV-2 spread in India. Full-length SARS-CoV-2 genome sequences of the circulating viruses from all over India were collected from GISAID, an open data repository, until 25thJuly, 2020. We have focused on the non-synonymous changes across the genome that resulted in amino acid substitutions. Analysis of the genomic signatures of the non-synonymous mutations demonstrated a strong association between the time of sample collection and the accumulation of genetic diversity. Most of these isolates from India belonged to the A2a clade (63.4%) which has overcome the selective pressure and is spreading rapidly across several continents. Interestingly a new clade I/A3i has emerged as the second-highest prevalent type among the Indian isolates, comprising 25.5% of the Indian sequences. Emergence of new mutations in the S protein was observed. Major SARS-CoV-2 clades in India have defining mutations in the RdRp. Maximum accumulation of mutations was observed in ORF1a.Other than the clade-defining mutations, few representative non-synonymous mutations were checked against the available crystal structures of the SARS-CoV-2 proteins in the DynaMut server to assess their thermodynamic stability. We have observed that SARS-CoV-2 genomes contain more uracil than any other nucleotide. Furthermore, substitution of nucleotides to uracil was highest among the non-synonymous mutations observed. The A+U content in SARS-CoV-2 genome is much higher compared to other RNA viruses, suggesting that the virus RdRp has a propensity towards uracil incorporation in the genome. This implies that thymidine analogues may have a better chance to competitively inhibit SARS-CoV-2 RNA replication than other nucleotide analogues.

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“…Another approach comprises the application of nucleoside analogues as antivirals [88]. For instance, several classes of nucleoside analogues were verified against SARS-CoV in Vero cells [89]. In the study, the D-isomer of thymine analogue exhibited strong anti-SARS-CoV activity and did not show any toxicity at the highest tested dosage of 100 µM.…”

Section: Therapeutic Agentsmentioning

confidence: 98%

Coronavirus Pandemic—Therapy and Vaccines

Lundström¹

2020

Biomedicines

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The current coronavirus COVID-19 pandemic, which originated in Wuhan, China, has raised significant social, psychological and economic concerns in addition to direct medical issues. The rapid spread of severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 to almost every country on the globe and the failure to contain the infections have contributed to fear and panic worldwide. The lack of available and efficient antiviral drugs or vaccines has further worsened the situation. For these reasons, it cannot be overstated that an accelerated effort for the development of novel drugs and vaccines is needed. In this context, novel approaches in both gene therapy and vaccine development are essential. Previous experience from SARS-and MERS-coronavirus vaccine and drug development projects have targeted glycoprotein epitopes, monoclonal antibodies, angiotensin receptor blockers and gene silencing technologies, which may be useful for COVID-19 too. Moreover, existing antivirals used for other types of viral infections have been considered as urgent action is necessary. This review aims at providing a background of coronavirus genetics and biology, examples of therapeutic and vaccine strategies taken and potential innovative novel approaches in progress.

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Antiviral Activity of Nucleoside Analogues against SARS-coronavirus (SARS-CoV)

Cited by 49 publications

References 22 publications

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

SARS-CoV-2 has observably higher propensity to accept uracil as nucleotide substitution: Prevalence of amino acid substitutions and their predicted functional implications in circulating SARS-CoV-2 in India up to July, 2020

Coronavirus Pandemic—Therapy and Vaccines

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