Broad spectrum antiviral nucleosides—Our best hope for the future

Seley‐Radtke, Katherine L.; Thames, Joy E.; Waters, Charles

doi:10.1016/bs.armc.2021.09.001

Cited by 12 publications

(13 citation statements)

References 124 publications

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“…Non-ribose backbone modifications including phosphorodiamidate morpholino oligonucleotides (PMOs) and peptide nucleic acids (PNAs) have shown promise as steric blocking antisense agents, and when conjugated with cell-penetrating peptides or molecules that facilitate delivery into mammalian cell systems via intravenous or intraperitoneal injection allow the rapid penetration of a wide range of cellular membranes and biophysical barriers including the blood-brain barrier (Lima et al, 2018 ; Nguyen et al, 2021 ; Walgrave et al, 2021 ). The use and details of these novel stability-augmenting chemistries for sncRNAs and miRNAs have been extensively discussed and reviewed over the last decade in a series of comprehensive studies and detailed reports some of which are listed here (Lennox and Behlke, 2011 ; De Clercq, 2013 ; Baigude and Rana, 2014 ; Evers et al, 2015 ; Elbarbary et al, 2017 ; Lima et al, 2018 ; Mai et al, 2019 ; Silva et al, 2020 ; Grabowska-Pyrzewicz et al, 2021 ; Groaz and De Jonghe, 2021 ; Seley-Radtke et al, 2021 ).…”

Section: The Modulation Of Microrna Stabilitymentioning

confidence: 99%

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

Lukiw

2022

Front. Neurosci.

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Section: The Modulation Of Microrna Stabilitymentioning

confidence: 99%

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

Lukiw

2022

Front. Neurosci.

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“…The successful usage ( Rubin et al, 2020 ) of nucleotide/nucleoside analog (NA) drugs in treating RNA virus related disease have emphasized the importance of this class of compounds in prevention and control of existing and future pathogens ( Furuta et al, 2013 ; Gane et al, 2013 ; Rubin et al, 2020 ). However, multiple factors including but not limited to the differences among RdRP active sites, differences in optimal prodrug forms targeting certain cell types, and emergence of drug-resistant virus strains determine the effectiveness of an NA on a certain virus and its broad-spectrum potential ( Feng and Ray, 2021 ; Jia et al, 2021 ; Seley-Radtke et al, 2021 ). Understanding the intervention mechanism of the NTP form of NA (the effective molecule in vivo ) at enzymology and structural levels is a key not only to identify repurposed NA drugs, but also to design new NA drugs ( Appleby et al, 2015 ; Xu et al, 2017 ).…”

Section: Rdrp Nac Regulation By Non-cognate Ntp or Ntp Analogsmentioning

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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“…Different antiviral mechanisms against SARS-CoV-2 may also be implicated in relation to the chemical, molecular weight and structural characteristics of L1, which has many similarities to the natural pyrimidine nuclear RNA bases of uracil and cytosine [ 171 , 172 ]. It is envisaged that such resemblance may result in inhibition similar to that observed by remdesivir, an antiviral drug with broad spectrum antiviral activity used in COVID-19 patients.…”

Section: Deferiprone Targeting Molecules and Metabolic Pathways Of Co...mentioning

confidence: 99%

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

Kontoghiorghes¹

2022

IJMS

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The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a “magic bullet” drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.

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Broad spectrum antiviral nucleosides—Our best hope for the future

Cited by 12 publications

References 124 publications

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

Fission Impossible: Stabilized miRNA-Based Analogs in Neurodegenerative Disease

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

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

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