{"89711":{"#nid":"89711","#data":{"type":"event","title":"Prof. Alan Spivey, Imperial College, London","body":[{"value":"\u003Cp\u003EProf. Alan Spivey, Imperial College, London\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003E\u003Cstrong\u003ESynthesis directed at the disruption of protein-protein interactions - asthma and cancer related targets\u003C\/strong\u003E\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003ESchool Colloquium\u003C\/p\u003E\u003Cp\u003ETwo projects will be described, both relating to synthetic efforts to\ndevelop small molecules to disrupt protein-protein interactions (PPIs) of\npotential medicinal importance. \u003C\/p\u003E\n\n\u003Cp\u003EThe first PPI we have been investigating is that\nbetween Immunolobulin E (IgE) (a protein found \u003Cem\u003Ee.g.\u003C\/em\u003E\nin the blood) and its high affinity receptor FceRI (a\nmembrane-bound protein found \u003Cem\u003Ee.g.\u003C\/em\u003E\non the surface of mast cells and basophils). This PPI is central to the\nallergic signal transduction cascade and so is a key target for potential\nanti-asthma therapeutics. Proof of principle that this strategy can be\neffective, and does not suffer from unacceptable side-effects, comes from the\nsuccessful clinical use of the monoclonal antibody Omalizumab (Xolair\u003Csup\u003E\uf7c5\u003C\/sup\u003E)\nwhich is indicated for severe persistent asthma and operates by sequestering\nIgE in the blood and preventing binding to FceRI.\nHowever, its high cost and non-oral mode of delivery has fuelled interest in\nthe development of alternative, small molecule antagonists of this PPI. We have\nbeen investigating approaches to disrupting this PPI based on both constrained\npeptides based on a hot spot epitope of IgE\u003Csup\u003E1\u003C\/sup\u003E and based on a natural\nproduct antagonist, aspercyclide A.\u003Csup\u003E2,3\u003C\/sup\u003E\u003C\/p\u003E\n\n\u003Cp\u003EThe second PPI we have been investigating is that\nbetween the Nuclear Receptor (NR) Liver Receptor Homologue-1 (LRH-1) and its\nvarious co-activator and co-repressor proteins such as the transcription activator\nPeroxisome Proliferator-Activated Receptor-\u03b3\nCo-activator (PGC)-1a. The\nregulation of transcription by these complexes has potential therapeutic\nbenefit in the context of breast cancer where LRH-1 has been implicated as\nhaving a role in modulating estrogen signalling.\u003Csup\u003E4\u003C\/sup\u003E The PPI centres on\nan interaction between an LXXLL a-helical motif in\nthe co-activator and a complimentary groove in the co-activator binding domain\n(AF2) of the NR. We have been investigating approaches to disrupting this PPI\nbased on rational design of a new a-helix mimetic motif.\u003C\/p\u003E\n\n\u003Cp\u003E\u003Cstrong\u003EReferences\u003C\/strong\u003E\u003C\/p\u003E\n\n\u003Cp\u003E1.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\nD.A. Offermann, J.E. McKendrick, J.J.P. Sejberg, B. Mo, M.D. Holdom, B.A. Helm,\nR.J. Leatherbarrow, A.J. Beavil, B.J. Sutton, A.C. Spivey, \u0027Synthesis and\nIncorporation into Cyclic Peptides of Tolan Amino Acids and their Hydrogenated\nCongeners: Construction of an Array of A-B-loop Mimetics of the C\u03b53 Domain of\nHuman IgE\u0027,\u003Cem\u003E\u003Cem\u003E J. Org.\nChem\u003C\/em\u003E\u003C\/em\u003E. \u003Cstrong\u003E\u003Cstrong\u003E2012\u003C\/strong\u003E\u003C\/strong\u003E, \u003Cem\u003E77\u003C\/em\u003E, ASAP.\u003Cbr \/\u003E2.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\nJ.L. Carr,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003ED.A.\nOffermann,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003EM.D.\nHoldom,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003EP. Dusart,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003EA.J.P. White,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003EA.J. Beavil,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003ER.J. Leatherbarrow,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003ES.D. Lindell,\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003EB.J. Sutton\u003Cem\u003E\u003Csup\u003E, \u003C\/sup\u003E\u003C\/em\u003EA.C. Spivey\u003Cem\u003E\u003Csup\u003E \u003C\/sup\u003E\u003C\/em\u003E\u0027Total\nSynthesis of (+\/-)-Aspercyclide A and its C19 Methyl Ether\u0027 \u003Cem\u003EChem. Comm\u003C\/em\u003E. \u003Cstrong\u003E2010\u003C\/strong\u003E, 1824-1826.\u003Cbr \/\u003E3.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\nJ.L. Carr, J.J.P. Sejberg, F. Saab, M.D. Holdom, A.M. Davies, A.J.P. White,\nR.J.Leatherbarrow, A.J. Beavil, B.J. Sutton, S.D. Lindell, A.C. Spivey,\n\u0027Synthesis of the C19 Methyl Ether of Aspercyclide A via Germyl-Stille\nMacrocyclisation and ELISA Evaluation of Both Enantiomers Following Optical\nResolution\u0027, \u003Cem\u003EOrg. Biomol. Chem\u003C\/em\u003E. \u003Cstrong\u003E2011\u003C\/strong\u003E, \u003Cem\u003E9\u003C\/em\u003E,\n6814-6824.\u003Cbr \/\u003E4.\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp;\nThiruchelvam, P.T.;\u0026nbsp; Lai, F.F.; Hua, H.;\nThomas, R.S.; Hurtado, A.; Hudson, W.; Bayly,A.R.; Kyle, F.J.; Periyasamy, M.;\nPhotiou, A.; Spivey,A.C.; Ortlund,E.A.; Whitby,R.J.; Carroll, J.S.; Coombes,\nR.C.; Buluwela, L.; Ali, S. \u0027The liver receptorhomolog-1 regulates estrogen\nreceptor expression in breast cancer cells\u0027 \u003Cem\u003EBreast\nCancer Res. Treat\u003C\/em\u003E. \u003Cstrong\u003E2010\u003C\/strong\u003E,\n\u003Cem\u003E127\u003C\/em\u003E, 385-396.\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EProf. Alan Spivey, Imperial College, London\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003E\u003Cstrong\u003ESynthesis directed at the disruption of protein-protein interactions - asthma and cancer related targets\u003C\/strong\u003E\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003ESchool Colloquium\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":"","uid":"27275","created_gmt":"2011-02-24 01:00:00","changed_gmt":"2016-10-08 01:50:45","author":"Shirley Tomes","boilerplate_text":"","field_publication":"","field_article_url":"","field_event_time":{"event_time_start":"2012-04-26T17:00:00-04:00","event_time_end":"2012-04-26T18:00:00-04:00","event_time_end_last":"2012-04-26T18:00:00-04:00","gmt_time_start":"2012-04-26 21:00:00","gmt_time_end":"2012-04-26 22:00:00","gmt_time_end_last":"2012-04-26 22:00:00","rrule":null,"timezone":"America\/New_York"},"extras":[],"related_links":[{"url":"http:\/\/www3.imperial.ac.uk\/people\/a.c.spivey","title":"Prof. Alan Spivey, Imperial College, London"}],"groups":[{"id":"85951","name":"School of Chemistry and Biochemistry"}],"categories":[],"keywords":[{"id":"89","name":"chemistry"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[{"id":"1795","name":"Seminar\/Lecture\/Colloquium"}],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003E\u003Cstrong\u003EShirley Tomes\u003C\/strong\u003E, \u003Ca href=\u0022http:\/\/www.gatech.edu\/contact\/index.html?id=st81\u0022\u003EContact Shirley Tomes\u003C\/a\u003E, \u003Cstrong\u003E404-894-0591\u003C\/strong\u003E\u003C\/p\u003E","format":"limited_html"}],"email":[],"slides":[],"orientation":[],"userdata":""}}}