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  • 1
    Online Resource
    Online Resource
    Identifying Inhibitors of −1 Programmed Ribosomal Frameshifting in a Broad Spectrum of Coronaviruses
    MDPI AG ; 2022
    In:  Viruses Vol. 14, No. 2 ( 2022-01-18), p. 177-
    Details
    In: Viruses, MDPI AG, Vol. 14, No. 2 ( 2022-01-18), p. 177-
    Abstract: Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates −1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of −1 PRF in SARS-CoV-2 also inhibited −1 PRF in a range of bat CoVs—the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on −1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed −1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit −1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v14020177
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2516098-9
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  • 2
    Online Resource
    Online Resource
    DataSheet1.docx
    Frontiers Media SA ; 2022
    In:  Frontiers in Chemistry Vol. 10 ( 2022-12-6)
    Details
    In: Frontiers in Chemistry, Frontiers Media SA, Vol. 10 ( 2022-12-6)
    Abstract: The economical and societal impact of COVID-19 has made the development of vaccines and drugs to combat SARS-CoV-2 infection a priority. While the SARS-CoV-2 spike protein has been widely explored as a drug target, the SARS-CoV-2 helicase (nsp13) does not have any approved medication. The helicase shares 99.8% similarity with its SARS-CoV-1 homolog and was shown to be essential for viral replication. This review summarizes and builds on existing research on inhibitors of SARS-CoV-1 and SARS-CoV-2 helicases. Our analysis on the toxicity and specificity of these compounds, set the road going forward for the repurposing of existing drugs and the development of new SARS-CoV-2 helicase inhibitors.
    Type of Medium: Online Resource
    ISSN: 2296-2646
    URL: Article
    URL: Article
    DOI: 10.3389/fchem.2022.1062352
    DOI: 10.3389/fchem.2022.1062352.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2711776-5
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  • 3
    Online Resource
    Online Resource
    Regulation of T7 gp2.5 binding dynamics by its C-terminal tail, template conformation and sequence
    Oxford University Press (OUP) ; 2023
    In:  Nucleic Acids Research Vol. 51, No. 13 ( 2023-07-21), p. 6540-6553
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 51, No. 13 ( 2023-07-21), p. 6540-6553
    Abstract: Bacteriophage T7 single-stranded DNA-binding protein (gp2.5) binds to and protects transiently exposed regions of single-stranded DNA (ssDNA) while dynamically interacting with other proteins of the replication complex. We directly visualize fluorescently labelled T7 gp2.5 binding to ssDNA at the single-molecule level. Upon binding, T7 gp2.5 reduces the contour length of ssDNA by stacking nucleotides in a force-dependent manner, suggesting T7 gp2.5 suppresses the formation of secondary structure. Next, we investigate the binding dynamics of T7 gp2.5 and a deletion mutant lacking 21 C-terminal residues (gp2.5-Δ21C) under various template tensions. Our results show that the base sequence of the DNA molecule, ssDNA conformation induced by template tension, and the acidic terminal domain from T7 gp2.5 significantly impact on the DNA binding parameters of T7 gp2.5. Moreover, we uncover a unique template-catalyzed recycling behaviour of T7 gp2.5, resulting in an apparent cooperative binding to ssDNA, facilitating efficient spatial redistribution of T7 gp2.5 during the synthesis of successive Okazaki fragments. Overall, our findings reveal an efficient binding mechanism that prevents the formation of secondary structures by enabling T7 gp2.5 to rapidly rebind to nearby exposed ssDNA regions, during lagging strand DNA synthesis.
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
    URL: Article
    DOI: 10.1093/nar/gkad485
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1472175-2
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Complex dynamics under tension in a high-efficiency frameshift stimulatory structure
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 39 ( 2019-09-24), p. 19500-19505
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 39 ( 2019-09-24), p. 19500-19505
    Abstract: Specific structures in mRNA can stimulate programmed ribosomal frameshifting (PRF). PRF efficiency can vary enormously between different stimulatory structures, but the features that lead to efficient PRF stimulation remain uncertain. To address this question, we studied the structural dynamics of the frameshift signal from West Nile virus (WNV), which stimulates −1 PRF at very high levels and has been proposed to form several different structures, including mutually incompatible pseudoknots and a double hairpin. Using optical tweezers to apply tension to single mRNA molecules, mimicking the tension applied by the ribosome during PRF, we found that the WNV frameshift signal formed an unusually large number of different metastable structures, including all of those previously proposed. From force-extension curve measurements, we mapped 2 mutually exclusive pathways for the folding, each encompassing multiple intermediates. We identified the intermediates in each pathway from length changes and the effects of antisense oligomers blocking formation of specific contacts. Intriguingly, the number of transitions between the different conformers of the WNV frameshift signal was maximal in the range of forces applied by the ribosome during −1 PRF. Furthermore, the occupancy of the pseudoknotted conformations was far too low for static pseudoknots to account for the high levels of −1 PRF. These results support the hypothesis that conformational heterogeneity plays a key role in frameshifting and suggest that transitions between different conformers under tension are linked to efficient PRF stimulation.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1905258116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Conformational Shannon Entropy of mRNA Structures from Force Spectroscopy Measurements Predicts the Efficiency of − 1 Programmed Ribosomal Frameshift Stimulation
    American Physical Society (APS) ; 2021
    In:  Physical Review Letters Vol. 126, No. 3 ( 2021-1-21)
    Details
    In: Physical Review Letters, American Physical Society (APS), Vol. 126, No. 3 ( 2021-1-21)
    Type of Medium: Online Resource
    ISSN: 0031-9007 , 1079-7114
    URL: Article
    DOI: 10.1103/PhysRevLett.126.038102
    RVK:
    UA 1000
    RVK:
    UA 6520
    Language: English
    Publisher: American Physical Society (APS)
    Publication Date: 2021
    detail.hit.zdb_id: 1472655-5
    detail.hit.zdb_id: 208853-8
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  • 6
    Online Resource
    Online Resource
    Unravelling How Single-Stranded DNA Binding Protein Coordinates DNA Metabolism Using Single-Molecule Approaches
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 3 ( 2023-02-01), p. 2806-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 3 ( 2023-02-01), p. 2806-
    Abstract: Single-stranded DNA-binding proteins (SSBs) play vital roles in DNA metabolism. Proteins of the SSB family exclusively and transiently bind to ssDNA, preventing the DNA double helix from re-annealing and maintaining genome integrity. In the meantime, they interact and coordinate with various proteins vital for DNA replication, recombination, and repair. Although SSB is essential for DNA metabolism, proteins of the SSB family have been long described as accessory players, primarily due to their unclear dynamics and mechanistic interaction with DNA and its partners. Recently-developed single-molecule tools, together with biochemical ensemble techniques and structural methods, have enhanced our understanding of the different coordination roles that SSB plays during DNA metabolism. In this review, we discuss how single-molecule assays, such as optical tweezers, magnetic tweezers, Förster resonance energy transfer, and their combinations, have advanced our understanding of the binding dynamics of SSBs to ssDNA and their interaction with other proteins partners. We highlight the central coordination role that the SSB protein plays by directly modulating other proteins’ activities, rather than as an accessory player. Many possible modes of SSB interaction with protein partners are discussed, which together provide a bigger picture of the interaction network shaped by SSB.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24032806
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Public Health Needs the Public Trust: A Pandemic Retrospective
    MDPI AG ; 2023
    In:  BioMed Vol. 3, No. 2 ( 2023-05-30), p. 256-271
    Details
    In: BioMed, MDPI AG, Vol. 3, No. 2 ( 2023-05-30), p. 256-271
    Abstract: The COVID crisis of the past three years has greatly impacted stakeholder relationships between scientists, health providers, policy makers, pharmaceutical industry employees, and the public. Lockdowns and restrictions of civil liberties strained an already fraught relationship between the public and policy makers, with scientists also seen as complicit in providing the justification for the abrogation of civil liberties. This was compounded by the suppression of open debate over contentious topics of public interest and a violation of core bioethical principles embodied in the Nuremberg Code. Overall, the policies chosen during the pandemic have had a corrosive impact on public trust, which is observable in surveys and consumer behaviour. While a loss of trust is difficult to remedy, the antidotes are accountability and transparency. This narrative review presents an overview of key issues that have motivated public distrust during the pandemic and ends with suggested remedies. Scientific norms and accountability must be restored in order to rebuild the vital relationship between scientists and the public they serve.
    Type of Medium: Online Resource
    ISSN: 2673-8430
    URL: Article
    DOI: 10.3390/biomed3020023
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 3136488-3
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  • 8
    Online Resource
    Online Resource
    Cancer Metabolism as a Therapeutic Target and Review of Interventions
    MDPI AG ; 2023
    In:  Nutrients Vol. 15, No. 19 ( 2023-10-01), p. 4245-
    Details
    In: Nutrients, MDPI AG, Vol. 15, No. 19 ( 2023-10-01), p. 4245-
    Abstract: Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu15194245
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2518386-2
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  • 9
    Online Resource
    Online Resource
    Strategies for the Management of Spike Protein-Related Pathology
    MDPI AG ; 2023
    In:  Microorganisms Vol. 11, No. 5 ( 2023-05-17), p. 1308-
    Details
    In: Microorganisms, MDPI AG, Vol. 11, No. 5 ( 2023-05-17), p. 1308-
    Abstract: In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury, their mechanisms, and their evidentiary basis.
    Type of Medium: Online Resource
    ISSN: 2076-2607
    URL: Article
    DOI: 10.3390/microorganisms11051308
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2720891-6
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