Leduc, Richard

Professeur, Faculté de médecine et des sciences de la santé
FMSS Département de pharmacologie-physiologie

Coordonnées

Courriel


819-821-8000, poste 75413

Diplômes

(1991) Postdoctorat (Biologie moléculaire / biologie cellulaire / Biochimie). Oregon Health Sciences University.

(1988) Doctorat (Sciences biomédicales / Biochimie). Université de Montréal.

(1982) Maîtrise avec mémoire (Pharmacologie - Maîtrise). Université de Sherbrooke.

(1980) Baccalauréat (Biochimie). Université de Sherbrooke.

Titres de compétence

(2019) Assistant Vice-dean for Knowledge Transfer. Université de Sherbrooke.

(2015) Director, Department of Pharmacology. Université de Sherbrooke.

Expérience académique

(2015) Assistant Vice-dean for Knowledge transfer. Université de Sherbrooke.

Présentation

Sujets de recherche

Molécules bioactives, Maladies hépatiques, Carcinogenèse, Maladies infectieuses, Cancer de la prostate, Maladies cardiovasculaires, Arthrite / arthrose.

Disciplines de recherche

Biochimie, Biologie cellulaire.

Mots-clés

Conception d'inhibiteurs de protéases, Expression cellulaire hétérologue et homologue, Ingénerie des protéines, Modèles cellulaires, Mutagénèse dirigée, peptidomimetics, Protéases à sérines, protein purification, enzymology, Relation structure-activité, Signalisation cellulaire.

Intérêts de recherche

Notre laboratoire se concentre sur des études de structure-activité de deux familles de cibles pharmacologiques situées à la membrane plasmique de la cellule soient les récepteurs couplés aux protéines G et les sérine protéases transmembranaires de type II. Par des approches de biologie moléculaire et de pharmacologie moléculaire nous tentons d'élucider comment fonctionnent ces protéines avec une vision de produire des composés thérapeutiques contre une variété de conditions pathologiques.

Centre de recherche

Centre de recherche du CHUS

Langues parlées et écrites

Anglais, Français

Financement

Subvention. (Obtenu). Co-demandeur. Impact of novel ubiquitin-based Galphas regulation on receptor signalling and trafficking (25% to be awarded to R. Leduc). Instituts de Recherche en Santé du Canada (IRSC). Project grant. 665550 $ (2019-2024).

Subvention. (Obtenu). Co-demandeur. Tumor-promoting functions of TMPRSS13 in breast cancer progression (5% to be awarded to R. Leduc). National Institutes of Health (NIH) (USA). RO1. 4000000 $ (2018-2023).

Subvention. (Obtenu). Co-demandeur. Targeting cancer stem cells to fight leukemia relapses (10% to be awarded to R. Leduc). Oncopole Quebec. Project program. 3000000 $ (2018-2023).

Subvention. (Obtenu). Collaborateur. Collaboration IRIC/ Universite/industrie: découverte accélérée de thérapies de l'économie pour un impact durable-FACS (2% to be awarded to R. Leduc). Gouvernement du Québec. FACS. 10000000 $ (2019-2022).

Subvention. (Terminé). Demandeur principal. Characterization of GPR3 as a novel pharmacological target for Alzheimer's disease. Société Alzheimer du Canada. Grant. 150000 $ (2016-2018).

Contrat. (Terminé). Demandeur principal. Development of TMPRSS6 inhibitors for iron overload diseases. GlaxoSmithKline. DPAC. 250000 $ (2015-2018).

Publications

Articles de revue

  • (supervised *) Béliveau, F.*, Tarkar, A.,Dion, S.P.*, Désilets, A.*, Ghinet, M.G.*, Boudreault, P.L., St-Georges, C.*, Marsault, É., Paone, D., Collins, J., Macphee, C.H., Campobasso, N., Groy, A., Cottom, J., Ouellette, M., Pope, A.J., and Leduc, R. (2019). Discovery and development of TMPRSS6 inhibitors modulating hepcidin levels in human hepatocytes. Cell Chemical Biology, 26, 1-14. (Article publié).
  • Connolly, A.*, Holleran, B.*, Simard, É.*, Baillargeon, J.P., Lavigne, P., and Leduc R. (2019). Interplay between intracellular loop 1 and helix VIII of the angiotensin II type 2 receptor controls its activation. Biochem Pharmacol, 168, 330-338. DOI. (Article publié).
  • St-Pierre, D.*, Cabana, J.*, Holleran, B.J.*, Besserer-Offroy, E.*, Escher, E., Guillemette, G., Lavigne, P., and Leduc R. (2018). Angiotensin II cyclic analogs as tools to investigate AT1R biased signaling mechanisms. Biochem Pharmacol, 154, 104-117 *supervised. DOI. (Article publié).
  • Ndong, D.B., Blais, V., Holleran, B.J., Proteau-Gagné, A., Cantin-Savoie, I., Robert, W., Nadon, J.F., Beauchemin, S., Leduc, R., Pineyro, G., Guérin, B., Gendron, L., and Dory, Y.L. (2018). Exploration of the fifth position ofLeu-enkephalin and its role in binding and activating delta (DOP) and mu (MOP)opioid receptors. Peptide Sci, x, y. (Article publié).
  • Dion, S.*, Béliveau, F.*, Morency, L.P., Désilets, A.*, Najmanovich, R., Leduc, R. (2018). Functional diversity of TMPRSS6 isoforms and variants expressed in hepatocellular carcinoma cell lines. Sci Rep, 8, 12562 *supervised. DOI. (Article publié).
  • Namkung Y., LeGouill C., Kumar S., Cao Y., Teixeira L.B., Lukasheva V., Giubilaro J., Simões S.C., Longpré J.M.*, Devost D., Hébert T.E., Piñeyro G., Leduc R., Costa-Neto C.M., Bouvier M., Laporte S.A. (2018). Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors. Sci Signal, 11, 1-20. DOI. (Article publié).
  • Tutunea-Fatan, E., Abd-Elrahman, K.S., Thibodeau, J.F., Holterman, C.E., Holleran, B.J.*, Leduc, R., Kennedy, C.R.J., Gros, R., Ferguson, S.S.G. (2018). GRK2 knockdown in mice exacerbates kidney injury and alters renal mechanisms of blood pressure regulation. Sci Rep, 8, 11415. DOI. (Article publié).
  • Sousbie, M.*, Besserer-Offroy, E.*, Brouillette, R.L., Longpré, J.M., Leduc, R., Sarret, P., Marsault, É. (2018). In search of the optimal macrocyclization site for neurotensin. ACS Med Chem Lett, 9, 227-232. DOI. (Article publié).
  • Lavenus, S.*, Simard, E.*, Besserer-Offroy, E.*, Froehlich, U., Leduc, R.#, and Grandbois, M#. # Co-corresponding authors. (2018). Label-free cell signaling pathway deconvolution of Angiotensin type 1 receptor reveals time-resolved G-protein activity and distinct AngII and AngIII/IV responses. Pharmacol Res, 18, 30320-30327. DOI. (Article publié).
  • Sousbie, M.*, Vivancos, M., Brouillette, R.L., Besserer-Offroy, E.*, Longpre, J.M., Leduc, R., Sarret, P., Marsault, E. (2018). Structural optimization and characterization of potent analgesic macrocyclic analogues of neurotensin 8-13. J Med Chem, 16, 7103-7115. DOI. (Article publié).
  • Besserer-Offroy, E.*, Berube, P., Cote, J., Murza, A., Longpre, J.M., Dumaine, R., Lesur, O., Auger-Messier, M., Leduc, R., Marsault, E and Sarret, P. (2018). The hypotensive effect of activated apelin receptor is correlated with beta-arrestin recruitment. Pharmacol Res, 131, 7-16. DOI. (Article publié).
  • Dion, S.P.*, Béliveau, F.*, Désilets, A.*, Ghinet, M.G.*, Leduc, R. (2018). Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities. J Cell Mol Med, 22, 2498-2509. DOI. (Article publié).
  • Li, X., Letourneau, D., Holleran, B.*, Leduc, R., Lavigne, P., Lavoie C. (2017). Galphas protein binds ubiquitin to regulate epidermal growth factor receptor endosomal signaling. Proc Natl Acad Sci USA, 114, 13477-13482. DOI. (Article publié).
  • Wilkinson, D.J, Habgood, A., Lamb, H.K., Thompson, P., Hawkins, A.R., Désilets, A.*, Leduc, R, Steinmetzer, T., Maya, H., Lee, M.S., Craik, C.S., Watson, S., Hua, L., Milner, J.M., Rowan, A.D. (2017). Matriptase induction of metalloproteinase-dependent aggrecanolysis in vitro and in vivo: promotion of osteoarthritic cartilage damage by multiple mechanisms. Arthritis Rheumatol., 69(8), 1601-1611. DOI. (Article publié).
  • St-Georges, C.*, Désilets, A.*, Béliveau, F.*, Ghinet, M.*, Dion, S.P*, Colombo, É.*, Boudreault, P.L., Najmanovich, R., Leduc, R and Marsault É. (2017). Modulating the selectivity of matriptase-2 inhibitors with unnatural amino acids. Eur J Med Chem, 129, 110-123. DOI. (Article publié).
  • Perreault, S., de Denus, S., White, M., White-Guay, B., Bouvier, M., Dorais, M., Dubé, M.P., Rouleau, J.L., Tardif, J.C., Jenna, S., Haibe-Kains, B., Leduc, R and Deblois, D. (2017). Older adults with heart failure treated with carvedilol, bisoprolol or metoprolol tartrate: risk of mortality. Pharmacoepidemiol Drug Saf, 26, 81-90. DOI. (Article publié).
  • Lahey, K.A., Ronaghan, J.J., Shang, J., Dion, S.P.*, Désilets, A.*, Leduc, R, MacNaughton, W.K. (2017). Signaling pathways induced by serine proteases to increase intestinal epithelial barrier function. PLoS One., 12(7), e0180259. DOI. (Article publié).
  • Murza, A., Sainsily, X., Côté, J., Bruneau-Cossette, L., Besserer-Offroy, E.*, Longpré, J.M., Leduc, R., Dumaine, R., Lesur, O., Auger-Messier, M., Sarret, P., and Marsault, É. (2017). Structure-activity relationship of novel macrocyclic biased apelin receptor agonists. Org Biomol Chem, 15, 449-458. DOI. (Article publié).
  • Pirisedigh, A., Blais, V., Ait-Mohand, S., Abdallah, K., Holleran, B.J.*, Leduc, R., Dory, Y.L., Gendron, L., Guérin, B. (2017). Synthesis and Evaluation of a 64Cu-conjugate, a selective delta-opioid receptor positron emission tomography imaging agent. Org Lett., 19, 2018-2021. DOI. (Article publié).
  • Wilkinson, D.J., Désilets, A.*, Falconer, A., Hsu, Y.C., Lin, H., Hawkins, A., Thompson, P., Ferrell, W.R., Plevin, R., Blain, E., Zhang, Y., Lin, S.W., Leduc, R., Milner, J.M., and Rowan, A.D. (2017). The serine protease hepsin is an activator of pro-matrix metalloproteinase: molecular mechanisms and implications for extracellular matrix turnover. Sci Rep, 7, 16693. DOI. (Article publié).
  • Besserer-Offroy, E.*, Brouillette, R.L., Lavenus, S.*, Froehlich, U., Brumwell, A.*, Murza, A., Longpré, J.M., Marsault, É., Grandbois, M., Sarret, P., Leduc, R. (2017). The signaling signature of the neurotensin type 1 receptor with endogenous ligands. Eur J Pharmacol., 805, 1-13. (Article publié).
  • Lanchec, E.*, Désilets, A.*, Béliveau, F.*, Flamier, A., Mahmoud, S., Bernier, G., Gris, D., Leduc, R.#, Lavoie, C.# # co-corresponding authors. (2017). The type II transmembrane serine protease matriptase cleaves the amyloid precursor protein and reduces its processing to ? amyloid. J Biol Chem, 292, 20669-20682. DOI. (Article publié).
  • Mona, C.E, Besserer-Offroy, E.*, Cabana, J., Leduc, R., Lavigne, P., Heveker, N., Marsault, É., and Escher, E. (2016). Design, synthesis and biological evaluation of CXCR4 ligands. Organic Biomol Chem, 14, 10298-10311. (Article publié).
  • Murza, A., Sainsily, X., Coquerel, D., Côté, J., Marx, P., Besserer-Offroy, É.*, Longpré, J.M., Lainé, J., Reversade, B., Salvail, D., Leduc, R., Dumaine, R., Auger-Messier, M., Lesur, O., Sarret, P. and Marsault, É. (2016). Discovery and structure-activity relationship of a bioactive fragment of ELABELA that modulates vascular and cardiac functions. J Med Chem, 59(7), 2962-2972. DOI. (Article publié).
  • Zoratti, G.L., Tanabe, L.M., Duhaime, M.J., Colombo, É.*, Leduc, R., Marsault, E., Johnson, M.D., Lin, C.Y., Boerner, J., Lang, J.E., List, K. (2016). Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer. Oncotarget, 7, 58162-58173. DOI. (Article publié).
  • Mona C.E., Besserer-Offroy É.*, Cabana J., Lefrançois M., Boulais P.E.*, Lefebvre M.R., Leduc R., Lavigne P., Heveker N., Marsault E., Escher E. (2016). Structure Activity Relationship and Signaling of New Chimeric CXCR4 Agonists. J Med Chem, 59, 7512-7524. DOI. (Article publié).
  • Monaghan, N.J., Shang, J., Iablokov, V., Zaheer, R., Colarusso, P., Dion, S.*, Désilets, A.*, Leduc, R., Turner, J.R., and MacNaughton, W.K. (2016). The serine protease-mediated increase in intestinal epithelial barrier function is dependent on occludin and requires an intact tight junction. Am J Physiology Gastrointest Liver Physiol, 311, G466-G479. DOI. (Article publié).
  • Perreault, S., de Denus, S., White, M., White-Guay, B., Bouvier, M., Dorais, M., Dubé, M.P., Rouleau, J., Tardif, J., Jenna, S., Haibe-Kains, B., Leduc, R., and Deblois, D. (2015). Association of Treatment with carvedilol, bisoprolol and metoprolol on the risk of mortality and hospital admission among older adults with heart failure. Value Health, 18, A379. DOI. (Article publié).
  • Murza, A., Besserer-Offroy, E.*, Côté, J., Bérubé, P., Longpré, J.M., Dumaine, R., Lesur, O., Auger-Messier, M., Leduc, R., Sarret, P., and Marsault, E. (2015). C-terminal modifications of apelin-13 significantly change ligand binding, receptor signaling and hypotensive action. J Med Chem, 58, 2431-2440. (Article publié).
  • Domazet, I., Holleran, B.J.*, Richard, A., Vandengerghe, C., Lavigne, P., Escher, E., Leduc, R. and Guillemette, G. (2015). Characterization of Angiotensin II molecular determinants involved in AT1 receptor functional selectivity. Mol Pharmacol, 87, 982-995. DOI. (Article publié).
  • Cabana, J., Holleran, B.*, Leduc, R., Escher, E., Guillemette, G., Lavigne, P. (2015). Identification of distinct conformations of the Angiotensin-II Type 1 receptor associated with the Gq/11 protein pathway and the beta-arrestin pathway using molecular dynamics simulations. J Biol Chem, 290, 15835-15854. DOI. (Article publié).
  • Lecointre, C., Desrues, L., Joubert, J.E., Perzo, N.*, Guichet, P.O., Lejoncour, V., Brulé, C.*, Chabbert, M., Leduc, R., Prézeau, L., Laquerrière, A., Proust, F., Gandolfo, P., Morin, F., and Castel, H. (2015). Signaling switch of the urotensin II receptor: Prototypic chemotaxic mechanism in glioma. Oncogene, 34, 5080-5094. DOI. (Article publié).
  • Fanelli, R., Besserer-Offroy, É.*, René, A., Côté, J., Tétreault, P., Collerette-Tremblay, J., Longpré, JM., Leduc, R., Martinez, J., Sarret, P., Cavelier, F. (2015). Synthesis and characterization in vitro and in vivo of (l)-(Trimethylsilyl)alanine containing neurotensin analogues. J Med Chem, 58, 7785-7795. DOI. (Article publié).
  • Zoratti, G., Tanabe, L., Varela, F., Murray, A.S., Berum, C., Colombo, E.*, Lang, J., Molinolo, A., Leduc, R., Marsault, É., Boerner, J., and List, K. (2015). Targeting matriptase in breast cancer abrogates tumor progression via impairment of stromal-epithelial growth factor signalling. Nature Commun, 6, 6776. DOI. (Article publié).
  • Duchene, D., Colombo, E.*, Désilets, A.*, Boudreault, P.L., Leduc, R., Marsault, É., Najmanovich, R. (2014). Analysis of sub-pocket selectivity and identification of potent selective inhibitors for matriptase and matriptase-2. J Med Chem, 57(23), 10198-204. DOI. (Article publié).
  • Brulé, C.*, Perzo, N.*, Joubert, J.E., Sainsily, X., Leduc, R.#, Castel, H.#, Prézeau, L.# (*co-corresponding senior authors). (2014). Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors. FASEB J, 28(12), 5148-5162. DOI. (Article publié).
  • Barré, O., Dufour, A., Béliveau, F.*, Leduc, R., Overall, C.M. (2014). Cleavage specificity analysis of type II transmembrane serine proteases (TTSPs) using PICS on proteome-derived peptide libraries. PLoS One, 9(9), e105984. DOI. (Article publié).
  • Demeule, M., Beaudet, N., Régina, A., Besserer-Offroy, E.*, Murza, A., Tétreault, P., Belleville, K., Ché, C., Larocque, A., Thiot, C., Béliveau, R., Longpré, J.M., Marsault, E., Leduc, R., Lachowicz, J., Gonias, S., Castaigne, J., Sarret, P. (2014). Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties. J Clin Invest, 124(3), 1199-213. DOI. (Article publié).
  • Sainsily, X., Cabana, J., Holleran, B.J.*, Escher, E., Lavigne, P., Leduc, R. (2014). Identification of transmembrane domain 1 & 2 residues that contribute to the formation of the ligand-binding pocket of the urotensin-II receptor. Biochem Pharmacol, 92(2), 280-8. DOI. (Article publié).
  • Tang, X., Mahajan, S.S., Nguyen, L.T., Béliveau, F.*, Leduc, R., Simon, J.A., Vasioukhin, V. (2014). Targeted inhibition of cell-surface serine protease Hepsin blocks prostate cancer bone metastasis. Oncotarget, 5(5), 1352-62. (Article publié).
  • Boulais, P.E.*, Escher, E., Leduc, R. (2013). Analysis by substituted cysteine scanning mutagenesis of the fourth transmembrane domain of the CXCR4 receptor in its inactive and active state. Biochem Pharmacol, 85(4), 541-50. DOI. (Article publié).
  • Cabana, J., Holleran, B.*, Beaulieu, M.È., Leduc, R., Escher, E., Guillemette, G., Lavigne, P. (2013). Critical hydrogen bond formation for activation of the angiotensin II type 1 receptor. J Biol Chem, 288(4), 2593-604. DOI. (Article publié).
  • Sainsily, X.*, Cabana, J., Boulais, P.E.*, Holleran, B.J.*, Escher, E., Lavigne, P., Leduc, R. (2013). Identification of transmembrane domain 3, 4 & 5 residues that contribute to the formation of the ligand-binding pocket of the urotensin-II receptor. Biochem Pharmacol, 86(11), 1584-93. DOI. (Article publié).
  • Beaulieu, A., Gravel, E., Cloutier, A., Marois, I., Colombo, E.*, Desilets, A.*, Verreault, C., Leduc, R., Marsault, E., Richter, M.V. (2013). Matriptase Proteolytically Activates Influenza Virus and Promotes Multicycle Replication in the Human Airway Epithelium. J Virol, 87(8), 4237-51. DOI. (Article publié).
  • Buzza, M.S., Martin, E.W., Driesbaugh, K.H., Désilets, A.*, Leduc, R., Antalis, T.M. (2013). Prostasin is required for matriptase activation in intestinal epithelial cells to regulate closure of the paracellular pathway. J Biol Chem, 288(15), 10328-37. DOI. (Article publié).
  • Fillion, D., Cabana, J., Guillemette, G., Leduc, R., Lavigne, P., Escher, E. (2013). Structure of the human angiotensin II type 1 (AT1) receptor bound to angiotensin II from multiple chemoselective photoprobe contacts reveals a unique peptide binding mode. J Biol Chem, 288(12), 8187-97. DOI. (Article publié).
  • Colombo, E.*, Désilets, A.*, Duchêne, D., Chagnon, F., Najmanovich, R., Leduc, R., and Marsault, E. (2012). Design and synthesis of potent, selective inhibitors of matriptase. ACS Med Chem Lett, 3(7), 530-534. (Article publié).
  • Murza, A., Parent, A., Besserer-Offroy, E.*, Tremblay, H., Karadereye, F., Beaudet, N., Leduc, R., Sarret, P., Marsault, É. (2012). Elucidation of the structure-activity relationships of apelin: influence of unnatural amino acids on binding, signaling, and plasma stability. ChemMedChem, 7(2), 318-25. (Article publié).
  • Netzel-Arnett, S., Buzza, M.S., Shea-Donohue, T., Désilets, A.*, Leduc, R., Fasano, A., Bugge, T.H., Antalis, T.M. (2012). Matriptase protects against experimental colitis and promotes intestinal barrier recovery. Inflamm Bowel Dis, 18(7), 1303-14. (Article publié).
  • Lefrançois, M., Lefebvre, M.R., Saint-Onge, G., Boulais, P.E.*, Lamothe, S., Leduc, R., Lavigne, P., Heveker, N., Escher, E. (2011). Agonists for the Chemokine Receptor CXCR4. ACS Med Chem Lett, 2(8), 596-602. (Article publié).
  • Béliveau, F.*, Brulé, C.*, Désilets, A*., Zimmerman, B., Laporte, S.A., Lavoie, C.L., Leduc, R. (2011). Essential role of endocytosis of the type II transmembrane serine protease TMPRSS6 in regulating its functionality. J Biol Chem, 286(33), 29035-43. (Article publié).
  • Bilodeau, J., Désilets, A.*, McDuff, F.O., St-Pierre, C.*, Barbar, E., Leduc, R., Lavigne, P. (2011). Influence of Ca2+ and pH on the folding of the prourotensin II precursor. FEBS Lett, 585(12), 1910-4. (Article publié).
  • Erwan Lanchec, Antoine Désilets, François Béliveau, Richard Leduc# and Christine Lavoie# #co-corresponding authors. Processing of APLP1 and APLP2 by the type II transmembrane serine protease matriptase. J Biol Chem, (Article soumis).

Propriétés intellectuelles

Brevets

  • Marsault, E., Richter, M., Leduc, R., Colombo, E. Matriptase inhibitors and uses thereof as anti-influenza agents. États-Unis. (Délivré).
  • Marsault, E., Leduc, R., Richter, M. Methods of using macrocycles as inhibitors of serine protease enzymes. PCT/US2010/053767. États-Unis. (Délivré).

Autres contributions

Cours enseignés

  • Advanced Biochemical Laboratory. BCM 503. Université de Sherbrooke. Niveau : Premier cycle.
  • Autacoïdes and hormones. PHR 702. Université de Sherbrooke. Niveau : Deuxième cycle.
  • Biomed I. Université de Sherbrooke. Niveau : Premier cycle.
  • Principes de Pharmacologie. PHR 701. Université de Sherbrooke. Niveau : Deuxième cycle.
  • Principles of neurotransmission. PHR 703. Université de Sherbrooke. Niveau : Deuxième cycle.
  • Seminars in Pharmacology. PHR 610. Université de Sherbrooke. Niveau : Deuxième cycle.

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