Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

Pastuch-Gawołek, Gabriela; Gillner, Danuta; Król, Ewelina; Walczak, Krzysztof; Wandzik, Ilona

doi:10.1016/j.ejphar.2019.172747

Cited by 32 publications

(32 citation statements)

References 108 publications

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“…Nucleoside/nucleotide-based inhibitors targeting viral DNA or RNA polymerase have been proven to be the backbone of antiviral therapies ( 5 – 8 ). Currently, there are over 25 approved therapeutic nucleosides/nucleotides used for the therapy of various viral infections of high medical importance, such as HIV infection (tenofovir, AZT, etc.…”

Section: Introductionmentioning

confidence: 99%

Development of a Simple In Vitro Assay To Identify and Evaluate Nucleotide Analogs against SARS-CoV-2 RNA-Dependent RNA Polymerase

Lu¹,

Zhang²,

Zheng³

et al. 2020

Antimicrob Agents Chemother

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Nucleotide analogs targeting viral RNA polymerase have been approved to be an effective strategy for antiviral treatment and are promising antiviral drugs to combat the current SARS-CoV-2 pandemic. In this report, we develop a robust in vitro nonradioactive primer extension assay to evaluate the incorporation efficiency of nucleotide analog by SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) quantitively. Our results show that many nucleotide analogs can be incorporated into RNA by SARS-CoV-2 RdRp, and that the incorporation of some of them leads to chain termination. The discrimination values of nucleotide analog over those of natural nucleotide were measured to evaluate the incorporation efficiency of nucleotide analog by SARS-CoV-2 RdRp. In agreement with the data published in literature, we found that the incorporation efficiency of remdesivir-TP is higher than ATP, and incorporation of remdesivir-TP caused delayed chain termination which can be overcome by higher concentrations of the following nucleotide to be incorporated. Our data also showed that the delay chain termination pattern caused by remdesivir-TP incorporation is different for different template sequence. Multiple incorporations of remdesivir-TP caused chain termination in our assay condition. Incorporation of sofosbuvir-TP is very low suggesting that sofosbuvir may not be very effective in treating SARS-CoV-2 infection. As a comparison, 2′-C-methyl-GTP can be incorporated into RNA efficiently, and the derivative of 2′-C-methyl-GTP may have therapeutic application in treating SARS-CoV-2 infection. This report provides a simple screening method that should be useful in evaluating nucleotide-based drugs targeting SARS-CoV-2 RdRp, and for studying the mechanism of action of selected nucleotide analog.

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Section: Introductionmentioning

confidence: 99%

Development of a Simple In Vitro Assay To Identify and Evaluate Nucleotide Analogs against SARS-CoV-2 RNA-Dependent RNA Polymerase

Lu¹,

Zhang²,

Zheng³

et al. 2020

Antimicrob Agents Chemother

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“…The possibility of these antiviral drugs acting as their Michael adducts in the active site of their targeted receptors is an open question raised by our results especially since the antiviral mechanism of action of these drugs is not completely defined. 36 Uridine/thymidine kinase activity may well be inhibited because of the 5′-hydroxyl being trapped as an unreactive Michael adduct in the active site. Following this hypothesis, the active site of the targeted enzyme should be more complementary to the cyclized form of the nucleoside drug providing the energy necessary to drive the unfavorable equilibrium toward the cyclonucleoside.…”

Section: Discussionmentioning

confidence: 99%

Intramolecular Michael Additions in Uridine Derivatives: Isolation of the Labile 5′O-C6 Cyclonucleoside

2020

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Uridine derivatives undergo a diastereospecific intramolecular hetero Michael addition onto uracil C6 to give cyclo-adducts. In contrast to the potent amine and thiol nucleophiles at the 5′ position of ribose, which readily give the N - and S -cyclonucleosides in good yields, the cyclization reaction from the “natural” 5′-hydroxyl is tedious and has so far been overlooked most probably because of the thermodynamic instability of the O -cyclo-adduct. Here, we show that the O -cyclonucleoside 1 can be isolated, although in low isolated yields, in acidic conditions following an original mechanism. Whether such cyclization reactions occur from biologically relevant pyrimidine-based nucleosides is an open question of interest. Given the structures of thymidine-based antiviral drugs, our results suggest a new hypothetical mode of action for these drugs.

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“…SBV is also combined with other antiviral drugs, such as ledipasvir, velpatasvir and voxilaprevir. 110 , 111 The structural similarity between SBV ( Fig. 3 ) and uridine allows that drug to act on HCV RdRp, incorporate itself into the viral RNA and terminate the synthesis of the nucleotide sequence.…”

Section: Drug Repurposing For Covid-19mentioning

confidence: 99%