Repurposing Nucleoside Analogs for Human Coronaviruses

Zandi, Keivan; Amblard, Franck; Musall, Katie; Downs-Bowen, Jessica; Kleinbard, Ruby; Oo, Adrian; Cao, Dong; Liang, Bo; Russell, Olivia; McBrayer, Tamara R.; Bassit, Leda; Kim, Baek; Schinazi, Raymond F.

doi:10.1128/aac.01652-20

Cited by 63 publications

(73 citation statements)

References 34 publications

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“…This mechanism was experimentally proven by Chien et al, who demonstrated that SARS-CoV-2 RdRp can incorporate the triphosphate forms of sofosbuvir and tenofovir, thus blocking the incorporation of further nucleotide triphosphates [ 141 ]. On the other hand, the studies performed by the group of Schinazi showed no antiviral effect for sofosbuvir against SARS-CoV-2 [ 142 ]. In contrast, a randomized controlled trial on COVID-19 patients showed that adding this drug to standard care significantly reduced hospital stay duration but did not have any statistically-significant benefit on mortality [ 143 ].…”

Section: Nucleoside Analogs As Anti-hcov Drugsmentioning

confidence: 99%

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

et al. 2021

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Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.

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Section: Nucleoside Analogs As Anti-hcov Drugsmentioning

confidence: 99%

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

et al. 2021

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“…In addition, it has a challenging pharmacological profile allowing intravenous administration only [39][40][41] . We demonstrate that the parent nucleoside GS-441524 [12][13][14][15][16] can "sterilize" H(s)AEC cultures from SARS-CoV2 as no rebound of the virus was noted several days after removal of the molecule. Differences in antiviral potencies of RDV and GS-441524 have been reported depending on the cell lines used, which correlates with the formation of the biologically active (5'-triphosphate) metabolite 12,13 .…”

Section: Discussionmentioning

confidence: 99%

“…Three nucleoside analogues that are known as inhibitors of SARS-CoV-2 replication were selected as reference for studies in HAEC cultures. These included GS-441524 [12][13][14][15][16] (the parent nucleoside of RDV), EIDD-1931 [16][17][18] (the active metabolite of Molnupiravir) and AT-511 17 [a guanosine nucleotide analogue with activity against hepatitis C virus (HCV)]. In order to select a suitable concentration range of these molecules to be used in the HAEC cultures, we first explored their effect in VeroE6 and Huh7 cell lines.…”

Section: Effect Of Selected Antivirals On Sars-cov-2 Replication In Hmentioning

confidence: 99%

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

Dan

Donckers

Vangeel

et al. 2021

Preprint

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There are, besides Remdesivir (RDV), no approved antivirals for the treatment and/or prophylaxis of SARS-CoV-2 infections. To aid in the search for antivirals against this virus, we explored the use of human tracheal airway epithelial cells (HAEC) and human small airway epithelial cells (HsAEC) grown at the air/liquid interface (ALI) and infected at the apical side with either one of two different SARS-CoV-2 isolates. The virus was shown to replicate to high titers for extended periods of time (at least 8 days) and, in particular an isolate with the D614G in the spike (S) protein did so more efficiently at 35°C than at 37°C. The effect of a selected panel of reference drugs that were added to the culture medium at the basolateral side of the system was explored. GS-441524 (the parent nucleoside of Remdesivir), EIDD-1931 (the active metabolite of Molnupiravir) and IFN (β1 and λ1) all resulted in a dose-dependent inhibition of viral RNA and infectious virus titers at the apical side. However, AT-511 (a guanosine nucleotide previously reported to inhibit SARS-CoV-2) failed to inhibit viral replication. Together, these results provide a reference for further studies aimed at selecting SARS-CoV-2 inhibitors for further preclinical and clinical development.

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“…Remdesivir is a nucleoside analog that acts as a small molecule inhibitor of an essential coronavirus enzyme complex, the RNA-dependent RNA polymerase (4). Nucleoside analogues are one of the largest and most effective classes of small molecule drugs against viruses like human immunodeficiency virus, hepatitis B virus and herpesviruses (5,6). The efficacy of remdesivir as a COVID-19 treatment remains controversial.…”

Section: Introductionmentioning

confidence: 99%

“…Besides remdesivir, several other clinically approved nucleoside analog compounds are currently under study for treating COVID-19. Molnupiravir (11,12) and AT-527 (13) are the most promising candidates so far, while ritonavir (14), ribavirin (15), favipiravir (16) and sofosbuvir (6,17) have not demonstrated significant antiviral effect against SARS-CoV-2 in laboratory or clinical settings.…”

Section: Introductionmentioning

confidence: 99%

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp12/7/8 RNA-dependent RNA Polymerase

Beale

Bertolin

Canal

et al. 2021

Preprint

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The coronavirus disease 2019 (COVID-19) global pandemic has turned into the largest public health and economic crisis in recent history impacting virtually all sectors of society. There is a need for effective therapeutics to battle the ongoing pandemic. Repurposing existing drugs with known pharmacological safety profiles is a fast and cost-effective approach to identify novel treatments. The COVID-19 etiologic agent is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded positive-sense RNA virus. Coronaviruses rely on the enzymatic activity of the replication-transcription complex (RTC) to multiply inside host cells. The RTC core catalytic component is the RNA-dependent RNA polymerase (RdRp) holoenzyme. The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologs in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer (FRET)-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified 3 novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.

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Repurposing Nucleoside Analogs for Human Coronaviruses

Cited by 63 publications

References 34 publications

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp12/7/8 RNA-dependent RNA Polymerase

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