Giguère, Patrick - University of Ottawa - Department of Biochemistry, Microbiology and Immunology

个人简介

B.Sc., University of Sherbrooke (1998) Ph.D., University of Sherbrooke (2007) Postdoctoral Fellowship, UNC-Chapel Hill (2012)

研究领域

Substances addressing the opioid receptor system are widely used pharmaceuticals for treatment of chronic pain and addictive disorders. Given the difficulties associated with opioid therapy (overdose, tolerance, addiction, respiratory depression and constipation) there is a need for safer narcotic analgesics. The delta-opioid receptor (δ-OR), a member of the G protein-coupled receptor (GPCR) opioid family, is well described for its role in pain perception and management. Interestingly, in clinical models, it also showed great potential as anti-depressor and also for the treatment of symptoms associated with spasmodic movements in the Parkinson's disease. However, the clinical use of δ-OR agonists is limited due to the generation of potentially life-threatening side effects (e.g. epileptic-like seizures). Therapeutic targeting of GPCR function has been one of the most successful approaches for drug discovery supported by the fact that nearly 50 % of prescribed therapeutics target GPCRs. Most recently, Dr. Giguère made the discovery that the presence of a sodium ion in a conserved cavity within the δ-OR selectively modulates arrestin recruitment at the receptor. Importantly, accumulating evidence suggests a prominent role of the arrestin-dependent signaling pathway in triggering most of the deleterious effects observed by targeting the opioid system. Dr. Giguère's research program seeks to: Use pharmacological, biochemical and structural approaches to develop a new level of understanding of opioid receptor molecular recognition, pharmacological and functional selectivity; Drug screening and design of novel functionally selective allosteric modulators of the opioid receptors; GPCR's enhanced tool box by the development of a novel synthetic biology platform and cell-based assay. The ultimate objective of his research is to generate distinct therapeutics that will uniquely modify their pharmacology in a medically meaningful way increasing their therapeutic efficacy with reduced harmful side effects.

近期论文

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Kroeze WK, Sassano MF, Huang XP, Lansu K, McCorvy JD, Giguère PM, Sciaky N, Roth BL. PRESTO-TANGO: an open-source resource for interrogation of the druggable human GPCR-ome. Nat Struct Mol Biol. 2015 Apr 20 Eyal Vardy, J. Elliott Robinson, Chia Li, Reid H. J. Olsen, Jeffrey F. DiBerto, Patrick M. Giguere, Flori M. Sassano, Xi-Ping Huang, Hu Zhu, Daniel J. Urban, Kate L. White, Joseph E. Rittiner, Nicole A. Crowley, Kristen E. Pleil, Christopher M. Mazzone, Philip D. Mosier, Juan Song, Thomas L. Kash, C. J. Malanga, Michael J. Krashes, Bryan L. Roth, A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior. Accepted, Neuron, D-14-01899 Cheng J, Giguère PM, Onajole OK, Lv W, Gaisin A, Gunosewoyo H, Schmerberg C, Pogorelov VM, Rodriguiz RM, Vistoli G, Wetsel WC, Roth BL, Kozikowski AP. Optimization of 2-phenylcyclopropylmethylamines as selective 5-HT2C agonists and their evaluation as antipsychotic agents. J Med Chem. 2015 Feb 26;58(4):1992-2002. Fenalti G, Zatsepin NA, Betti C, Giguere P, Han GW, Ishchenko A, Liu W, Guillemyn K, Zhang H, James D, Wang D, Weierstall U, Spence JC, Boutet S, Messerschmidt M, Williams GJ, Gati C, Yefanov OM, White TA, Oberthuer D, Metz M, Yoon CH, Barty A, Chapman HN, Basu S, Coe J, Conrad CE, Fromme R, Fromme P, Tourwé D, Schiller PW, Roth BL, Ballet S, Katritch V, Stevens RC, Cherezov V. Structural basis for bifunctional peptide recognition at human δ-Opioid receptor. Nat Struct Mol Biol. 2015 Mar;22(3):265-8. Giguère PM, Gall BJ, Ezekwe EA Jr, Laroche G, Buckley BK, Kebaier C, Wilson JE, Ting JP, Siderovski DP, Duncan JA. G protein signaling modulator 3 inhibits the inflammasome activity of NLRP3. J Biol Chem. 2014 Nov 28;289(48):33245-57. Jianjun Cheng, Patrick M. Giguere, Wei Lv, Bryan L. Roth and Alan P. Kozikowski. Design and Synthesis of (2-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)cyclopropyl)methanamine as a Selective Serotonin 2C Agonist. Accepted,In Press Tetrahedron Letters TETL-D-14-02816R1 (http://www.sciencedirect.com/science/article/pii/S0040403915000751) Fenalti G*, Giguere PM*, Katritch V, Huang XP, Thompson AA, Cherezov V, Roth BL, Stevens RC. Molecular Control of δ-Opioid Receptor Signaling. *Contributed equally. Nature. 2014 Feb 13;506(7487):191-6 (2014: Signaling Breakthroughs of the Year, Sci. Signal., 6 January 2015 Vol. 8, Issue 358, p. eg1; Featured in Sci. Signal., 18 February 2014 Vol. 7, Issue 313, p. ec45 ; F1000 top 10 and F1000 must read, Highlighted by more than 50 news articles). Giguere PM, Kroeze WK and Roth BL. Tuning up the right signal: chemical and genetic approaches to study GPCR functions. Curr Opin Cell Biol. 2014 Apr;27C:51-55. Lee HM, Giguere PM and Roth BL. DREADDs: novel tools for drug discovery and development. Drug Discov Today. 2014 Apr;19(4):469-73. Giguère PM, Billard MJ, Laroche G, Buckley BK, Timoshchenko RG, McGinnis MW, Esserman D, Foreman O, Liu P, Siderovski DP and Tarrant TK. G-protein signaling modulator-3, a gene linked to autoimmune diseases, regulates monocyte function and its deficiency protects from inflammatory arthritis. Mol Immunol. 2012 Dec 29;54(2):193-198 Bosch DE, Kimple AJ, Muller RE, Giguère PM, Machius M, Willard FS, Temple BR and Siderovski DP. Heterotrimeric G-protein signaling is critical to pathogenic processes in Entamoeba histolytica. PLoS Pathog. 2012 Nov;8(11) Giguère PM, Laroche G, Oestreich EA and Siderovski DP. Regulation of the subcellular localization of the G-protein regulator GPSM3 through direct association with 14-3-3. J Biol Chem. 2012 Sep 7;287(37):31270-9 Lei Y, Wen H, Yu Y, Taxman DJ, Zhang L, Widman DG, Swanson KV, Wen KW, Damania B, Moore CB, Giguère PM, Siderovski DP, Hiscott J, Razani B, Semenkovich CF, Chen X and Ting JP. The mitochondrial proteins NLRX1 and TUFM form a complex that regulates type I interferon and autophagy. Immunity, 2012 Jun 29;36(6):933-46 Giguère PM, Laroche G, Oestreich EA and Siderovski DP. GPSM3 regulates heterotrimer G protein dynamics through a dual association with Gβ and Gαi subunits. J Biol Chem. 2012 Feb 10;287(7):4863-74 Kimple AJ, Bosch DE, Giguère PM, and Siderovski DP. RGS Proteins and Their G-alpha Substrates: Promises and Challenges in Their Use as Drug Discovery Targets. Pharmacological Reviews, 2011 Sep;63(3):728-49. Laroche G, Giguère PM, Roth BL, Trejo J and Siderovski DP. RNA interference screen for RGS protein specificity at muscarinic and protease-activated receptors reveals bidirectional modulation of signaling. Am J Physiol Cell Physiol. 2010 Sep;299(3):C654-64 Kimple AJ, Willard FS, Giguère PM, Johnston CA, Mocanu V and Siderovski DP. The RGS protein inhibitor CCG-4986 is a covalent modifier of the RGS4 Galpha-interaction face. Biochim Biophys Acta. 2007 Sep;1774(9):1213-20 Laroche G, Giguère PM, Dupré E, Dupuis G and Parent JL. The N-terminal coiled-coil domain of the cytohesin/ARNO family of guanine nucleotide exchange factors interacts with Gαq. Mol Cell Biochem. 2007 Dec;306(1-2):141-52 Giguère P, Rochdi MD, Laroche G, Dupré E, Whorton M, Sunahara R, Claing A, Dupuis G and Parent JL. ARF6 activation by Gαq signaling: Gαq forms molecular complexes with ARNO and ARF6. Cell Signal. 2006 Nov;18(11):1988-94.