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Prion Chemical Biology: Where we are and where we will go?

Prion Chemical Biology: Where we are and where we will go? . Dr Beining Chen University of Sheffield PCBNet Launch Meeting, 12-13 September 2011. Prion Protein – good and bad . TSEs. Alzheimer’s diseases. Cancer. PrP C. Inflammation. Stem Cell. T-cell Activation. Memory.

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Prion Chemical Biology: Where we are and where we will go?

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  1. Prion Chemical Biology: Where we are and where we will go? Dr Beining Chen University of Sheffield PCBNet Launch Meeting, 12-13 September 2011

  2. Prion Protein – good and bad TSEs Alzheimer’s diseases Cancer PrPC Inflammation Stem Cell T-cell Activation Memory Iron Intake

  3. Physiology and Development PrPC Aging and Diseases

  4. Prion Chemical Biology Network (PCBNet) Theme Map • PrPC in Development and Ageing Related Conditions Chemistry Biology Target Deconvolution Translational Studies Small Molecule Chemical Tools Target Modulation Intersection of Molecules Animal studies Ligation techniques Systems biology Chemical libraries and synthesis Protein conformation In vitro and In vivo screening Binding partner and interaction Molecular trafficking Human clinic studies Proteomics Metabolomics Chemo-informatics Protein localisation Molecular delivery Sociology/ethic studies Chemo-genomics

  5. Prion Chemical Biology: Where we are?

  6. PrPC

  7. Small Molecules PrPC

  8. Techniques used to discover small molecule probes/therapeutics for TSE • Source of Small Molecules • Random chemical and natural product libraries • Computer aided selection of targeted chemical libraries • Individually synthesised libraries

  9. Techniques used to discover small molecule probes/therapeutics for TSE • Screening Assays • In vitro direct interaction assays • SPR • NMR • CD • ITC • Fluorescence • Cellular screening • In vivo assays • Mouse model • Larger animal

  10. Small Molecules

  11. Vehicle Control (DMSO)

  12. Small Molecules Direct in vitro Interaction with PrPC Biological Output i.e. cell line activity Anti TSE SAR observed In some models only No SAR observed ? Mode of Action

  13. Target deconvolution - System Biology

  14. Target deconvolution - Proteomics

  15. Interacting Partners Protein disulfide isomerase -3 Elongation factor-2 1-alpha-1 Serpin H1 Stress -70 protein Peroxiredoxin -1 Glutathione S-transferase-1 Transgelin-2 Glucose regulated protein Actin GAPDH Annexin 2 Tublina-1A Vimentin Triphosphate isomerase Tublin b-5 chain Stress induced Phosphoprotein 1 Beta-actin like protein-2 Malate dehydrogenase PrPC GrpE protein homologue -1 L- lactate Dehydrogenase A chain Peptidyl-prolyl cis-trans isomerase ADP ribosylation Factor 1 14-3-3 proteins , ,  HsP60 Lamin receptors Cofilin-1 Annexin A1, A5 Fructose-bisphosphate aldolase Rab7a Aspartate aminotransferase endoplasmin HSP 90-a and b a-enolase

  16. Small Molecules ? PrPC

  17. Small Molecules In vitro Assay Cell model Mouse model Drosophila Cell model Mouse model Zebra Fish PrPC

  18. Prion Chemical Biology: Where we will go?

  19. Chemical Biology Network (PCBNet) Theme Map

  20. Questions to be answered • Despite progress in TSEchemical biology, we still lack high affinity PrPc specific compounds, which are also potent in biological models. • What new approaches are open to us? Top down or bottom up? • Is PrPC the right target? Should we also take a more peripheral approach, i.e. prion related pathway/interacting partners? • What are the synergies and distinctions amongst TSE prion chemical biology, AD and and other amyloid diseases?

  21. Questions to be answered • What are the key biological questions to be addressed when studying the role of PrPC in stem cell and development? How can chemical biology help? • What are the current funding opportunities? How can we build strong consortia ready for applying for major funding? What are the priorities? • What are the key capacity and resources we need to build and share within the network if we were to fully understand the role of PrPC in these processes and develop appropriate therapeutics?

  22. Thank you! Any other suggestions?

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