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GuideToImmunopharmacology_SIF_Nov2019

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Presentation by Dr. Elena Faccenda on the IUPHAR/BPS Guide to Immunopharmacology at the 39° Congresso Nazionale della Società Italiana di Farmacologia in Florence, Nov 2019

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GuideToImmunopharmacology_SIF_Nov2019

  1. 1. IUPHAR/BPS Guide to IMMUNOPHARMACOLOGY Elena Faccenda University of Edinburgh, UK https://www.guidetopharmacology.org 39° CONGRESSO NA ZIONALE DELLA SOCIETÀ I TALIANA DI FARMACOLOGIA FIRENZE, 20 -23 NOVEMBRE, 2019 1WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  2. 2. Overview 2 • History of the Guide to PHARMACOLOGY • How to use the Guide • Development of the Guide to IMMUNOPHARMACOLOGY • How to view immuno-relevant content • A case study: cardiovascular inflammation WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  3. 3. History of the Guide to PHARMACOLOGY 3 GtoPdb has its origins in IUPHAR-DB and the BPS 'Guide to Receptors and Channels’ These were merged to form a single, online, free-to-access resource Expert-curated resource of ligand-activity-target relationships, selected from high-quality pharmacological and medicinal chemistry literature, under the oversight of target family-oriented subcommittees of leading scientists from around the globe ALL data is manually curated to maintain reliability and integrity WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  4. 4. Concise Guide to PHARMACOLOGY 4 The ‘Concise Guide to PHARMACOLOGY’ is generated from the database as a snapshot of content, and published by the British Journal of Pharmacology every two years A set of 7 open access pdfs; ~500 pages; PMIDs: 31710713-9 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  5. 5. How to use the GtoPdb 5 Browsing Search options Content overview WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  6. 6. GtoPdb content: targets 6 TT • Total number of targets: 2937 • Number of curated binding constants: 31207 • Human targets of approved drugs: 638 • Number of references: 36613 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  7. 7. GtoPdb content: ligands 7 • Total number of ligands: 9856 • Number of approved drugs: 1448 • Human targets of approved drugs: 638 • Ligands with quantitative interactions: 7486 • Ligands with clinical use summary: 2456 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  8. 8. GtoPdb browsing 8WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Links to browse target and ligand lists by category Database search Menu-bar
  9. 9. 9WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Target family level
  10. 10. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 10 Target subfamily level Links to detailed pages for each target Expandable summary views for each target
  11. 11. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 11 Detailed target page
  12. 12. Searching the entire database WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 12 Database search
  13. 13. 13WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Search results are downloadable
  14. 14. Other searches 14 Advanced search WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  15. 15. 15 Advanced search: targets UniProt ChEMBL Ensembl HGNC ID/symbol MGI ID/symbol RGD ID/symbol RefSeqs Entrez Gene ID WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  16. 16. 16 Advanced search: ligands BindingDB CAS registry number ChEBI ChEMBL ligand ID DrugBank IMGT/mAb-DB InChIs PDB IDs PubChem CID WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  17. 17. 17 Advanced search: pharmacology UniProt ChEMBL Ensembl HGNC ID/symbol MGI ID/symbol RGD ID/symbol RefSeqs Entrez Gene ID WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  18. 18. The Guide to IMMUNOPHARMACOLOGY 18 Developed to deliver a knowledge-base that connects immunology with pharmacology GtoImmuPdb is a Wellcome Trust-funded extension to the existing GtoPdb 1. Extended GtoPdb to contain key immunological data types and associate these with existing targets and ligands 2. Developed a new portal to provide an immunologist-friendly access-point to the data to allow easy browsing and searching 3. Continuing to curate new targets and pharmacological interactions WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  19. 19. How to view immuno-relevant content 19 Links directly to the GtoImmuPdb homepage WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  20. 20. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 20 Portal Panels to browse to target and ligand lists by category Database search Menu-bar
  21. 21. 21 Access from the GtoPdb WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Toggles ‘on’ the GtoImmuPdb view and highlights immuno-tagged targets
  22. 22. 22WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Subfamily level Target level With links to detailed target pages Immunopharmacology relevant families are highlighted
  23. 23. New data types in GtoImmuPdb 23WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Processes- using Gene Ontology (GO) Cell Types- using Cell Ontology
  24. 24. 24 Processes WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  25. 25. 25WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  26. 26. 26WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Cell types
  27. 27. 27WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG Use drop down list to select a different cell type Use links to jump to a specific target class
  28. 28. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 28 Inflammatory and immune-mediated diseases can be viewed as a discrete list Updated disease curation
  29. 29. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 29
  30. 30. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 30
  31. 31. A case study: targeting cardiovascular inflammation 31 Experimental data shows a causal role by immune and inflammatory responses in the initiation and development of atherosclerosis, but there are no immunomodulatory treatment in routine use. The CANTOS Phase 3 trial was the first to demonstrate that blockade of the IL-1b innate immune pathway could achieve clinical efficacy in reducing recurrent cardiovascular events in at risk patients Ridker et al. (2017) NEJM 377(12): 1119-1131 (PMID: 28845751) Could efficacy be improved by targeting other elements of the IL-1b pathway? What information does the GtoImmuPdb contain that could inform further research? WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  32. 32. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 32 Clinical data tab contains curated information about clinical use and molecular mechanism of action. Summary tab describes the ligand, its ‘type’, synonyms, whether it’s an approved drug, and links to external resources
  33. 33. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 33 The CANTOS studyBiological activity and Immunopharmacology tabs contain curated information about the ligand’s pharmacology and immunological context
  34. 34. Potential mechanisms to modulate the IL-1b pathway 34 (i) Control synthesis and release by the NALP3-inflammasome (ii) Control the membrane receptor and signalling (iii) Modulate signal transduction downstream of the activated receptors e.g. IRAKs 1, 2 & 4, IKK1/2, TAK1, MEKK3, JNK (->IL-6 & IL-8 expression), p38 MAPK (iv) Modulate activity of other pleiotropic IL-1 family cytokines associated with chronic inflammatory and autoimmune diseases e.g. IL-18 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  35. 35. Potential mechanisms to modulate the IL-1b pathway 35 (i) Control synthesis and release by the NALP3-inflammasome (ii) Control the membrane receptor and signalling (iii) Modulate signal transduction downstream of the activated receptors e.g. IRAKs 1, 2 & 4, IKK1/2, TAK1, MEKK3, JNK (->IL-6 & IL-8 expression), p38 MAPK (iv) Modulate activity of other pleiotropic IL-1 family cytokines associated with chronic inflammatory and autoimmune diseases e.g. IL-18 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  36. 36. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 36 There is evidence of pharmacological modulation of NLRP3 in GtoImmuPd, including evidence that one inhibitor (dapansutrile) is a clinical lead for autoinflammatory disease and heart failure
  37. 37. Potential mechanisms to modulate the IL-1b pathway 37 (i) Control synthesis and release by the NALP3-inflammasome (ii) Control the membrane receptor and signalling (iii) Modulate signal transduction downstream of the activated receptors e.g. IRAKs 1, 2 & 4, IKK1/2, TAK1, MEKK3, JNK (->IL-6 & IL-8 expression), p38 MAPK (iv) Modulate activity of other pleiotropic IL-1 family cytokines associated with chronic inflammatory and autoimmune diseases e.g. IL-18 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  38. 38. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 38 IL-1b ligand blockade IL-1 receptor inhibitors There is evidence of alternative mechanisms that validate the druggability of IL-1 pathway in GtoImmuPdb, including the IL-1 cytokine trap rilonacept and the IL-1 receptor antagonist peptide mimic anakinra
  39. 39. Potential mechanisms to modulate the IL-1b pathway 39 (i) Control synthesis and release by the NALP3-inflammasome (ii) Control the membrane receptor and its signalling (iii) Modulate signal transduction downstream of the activated receptors e.g. IRAKs 1, 2 & 4, IKK1/2, TAK1, MEKK3, JNK (->IL-6 & IL-8 expression), p38 MAPK (iv) Modulate activity of other pleiotropic IL-1 family cytokines associated with chronic inflammatory and autoimmune diseases e.g. IL-18 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  40. 40. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 40 Downstream pathway disruption via IRAK4 inhibition Selective IRAK4 inhibitors are identified by The Pfizer inhibitor is a clinical lead for RA So again evidence indicates that this is a druggable target in the pathway
  41. 41. Potential mechanisms to modulate the IL-1b pathway 41 (i) Control synthesis and release by the NALP3-inflammasome (ii) Control the membrane receptor and signalling (iii) Modulate signal transduction downstream of the activated receptors e.g. IRAKs 1, 2 & 4, IKK1/2, TAK1, MEKK3, JNK (->IL-6 & IL-8 expression), p38 MAPK (iv) Modulate activity of other pleiotropic IL-1 family cytokines associated with chronic inflammatory and autoimmune diseases e.g. IL-18 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  42. 42. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 42 Inhibition of IL-18 activity Tadekinig alfa is a recombinant IL-18 binding protein that acts as a functional antagonist of IL-18 activity. It is a clinical lead (Ph3) for IL-18-driven MAS-like syndrome. So again evidence indicates that this is a druggable target in the IL-1 pathway.
  43. 43. WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 43 Case study: Summary The GtoImmuPdb contains curated evidence which supports the proposition that modulation of targets at different levels of the IL-1 pathway have anti-inflammatory outcomes, and that these mechanisms could be translated to the search for novel approaches to reduce vascular inflammation in cardiovascular disease.
  44. 44. Conclusions WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 44 The GtoImmuPdb provides portal that is designed to be immunologist friendly. It brings together pharmacological data for targets and ligand interactions and links targets to immunological processes and immune cells types, and ligands/drugs to immune/inflammatory diseases. The GtoPdb and the GtoImmuPdb are open access resources whose curated content offers utility in experimental design and as well as potential in therapeutic programme development.
  45. 45. Guide to MALARIA PHARMACOLOGY 45 Developed with funding and scientific support from the Medicines for Malaria Venture (MMV) https://www.guidetomalariapharmacology.org/malaria/index.jsp WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  46. 46. 46WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  47. 47. 47 More extensive details are available in PMID: 29149325 Email enquiries@guidetopharmacology.org or e.faccenda@ed.ac.uk Twitter @GuidetoPHARM Blog https://blog.guidetopharmacology.org PMID: 31691834 WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG
  48. 48. Acknowledgements WWW.GUIDETOPHARMACOLOGY.ORG | WWW.GUIDETOIMMUNOPHARMACOLOGY.ORG 48 Scientific Advisors for IUPHAR GtoImmuPdb Stephen P.H. Alexander, UK Stephen Anderton, UK Clare Bryant, UK Anthony P. Davenport, UK Jamie A. Davies, UK Christian Doerig, Australia Doriano Fabbro, Switzerland Francesca Levi-Schaffer, Israel Michael Spedding, France Database Development and Curation Simon D. Harding, Senior Database Developer, UK Elena Faccenda, Database Curator, UK Adam Pawson, Senior Database Curator, UK Christopher Southan, Database Curator, UK • Expert subcommittees • the IUPHAR ImmuPhar Section • Pasquale Maffia, Institute of Infection, Immunity & Inflammation, University of Glasgow • Adriano Rossi, Centre for Inflammation Research, University of Edinburgh

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