Now showing 1 - 6 of 6
  • Publication
    Anti-prion drug mPPIg5 inhibits PrPC conversion to PrPSc
    Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The 'protein only hypothesis' advocates that PrPSc, an abnormal isoform of the cellular protein PrPC, is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrPSc in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrPC to PrPSc conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future.
      385Scopus© Citations 25
  • Publication
    Influence of surface functionality of poly(propylene imine) dendrimers on protease resistance and propagation of the scrapie prion protein
    Accumulation of PrP(Sc), an insoluble and protease-resistant pathogenic isoform of the cellular prion protein (PrP(C)), is a hallmark in prion diseases. Branched polyamines, including PPI (poly(propylene imine)) dendrimers, are able to remove protease resistant PrP(Sc) and abolish infectivity, offering possible applications for therapy. These dendrimer types are thought to act through their positively charged amino surface groups. In the present study, the molecular basis of the antiprion activity of dendrimers was further investigated, employing modified PPI dendrimers in which the positively charged amino surface groups were substituted with neutral carbohydrate units of maltose (mPPI) or maltotriose (m3PPI). Modification of surface groups greatly reduced the toxicity associated with unmodified PPI but did not abolish its antiprion activity, suggesting that the presence of cationic surface groups is not essential for dendrimer action. PPI and mPPI dendrimers of generation 5 were equally effective in reducing levels of protease-resistant PrP(Sc) (PrP(res)) in a dose- and time-dependent manner in ScN2a cells and in pre-existing aggregates in homogenates from infected brain. Solubility assays revealed that total levels of PrP(Sc) in scrapie-infected mouse neuroblastoma (ScN2a) cells were reduced by mPPI. Coupled with the known ability of polyamino dendrimers to render protease-resistant PrP(Sc) in pre-existing aggregates of PrP(Sc) susceptible to proteolysis, these findings strongly suggest that within infected cells dendrimers reduce total amounts of PrP(Sc) by mediating its denaturation and subsequent elimination.
      655Scopus© Citations 80
  • Publication
    Differentiating prion strains using dendrimers
    A panel of repetitively branched synthetic molecules known as dendrimers is used to identify and differentiate between different strains of the prion infectious agent, the protein-based pathogen responsible for prion disorders—a group of invariably fatal neurodegenerative diseases
      454Scopus© Citations 20
  • Publication
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  • Publication
    Influence of Surface Groups on Poly(propylene imine) Dendrimers Antiprion Activity
    Prion diseases are characterized by the accumulation of PrP(Sc), an aberrantly folded isoform of the host protein PrP(C). Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP(Sc) in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP(Sc) in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP(Sc) by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups.
      756Scopus© Citations 44
  • Publication
    Inclusive Teaching & Learning Case Studies in Engineering, Architecture & Affiliated Disciplines
    Diversity and inclusion are core to UCD values. We seek to attract students from a wide range of social and economic backgrounds and students who reflect the true diversity of the country. And as a global university, UCD attracts international students from over 100 countries. This diversity enriches our campus, and the experience of our students. The University's strategy 2020-2024 'Rising to the Future' also recognises the importance of inclusion and diversity, in seeking to "provide an inclusive educational experience that defines international best practice and prepares our graduates to thrive in present and future societies." However, an inclusive educational experience will not be achieved by simply creating diversity in the student body. It requires that we adjust our approach in everything we do to support and encourage our students’ success. We have clearly articulated in our strategy, and further emphasised in our Education and Student Success strategy, that our goal is to "equip all our educators with the tools and resources required to embed Universal Design for Learning on an institution-wide basis".
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