Biogenesis of peptide signals (BIOSIPE)

Bioactive peptides (neuropeptides, hormones, etc.) are involved in many physiological and pathophysiological processes, including cardiovascular diseases, obesity and Alzheimer. They are generally produced by limited proteolysis of precursor peptides. Proteolytic processing regulates not just the peptide activities, but may also be a source of structural and functional diversity. Nearly one million of different peptides are present in human tissues, less than one hundred have been characterized to date.

The research project of the team is to extend the known repertoire of signal peptides and cellular targets using:

  • i) identification of novel peptide effectors involved in the innate immunity;
  • ii) structural and functional characterization of a bi-functional processing enzyme. Another aspect of our research focuses on ecdysteroids, which represent hormones in insects, molecules of defense in plants, and pharmacological agents in the context of laboratory research developed in collaboration with Biophytis Institute.

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Each newly discovered bioactive molecule adds to our knowledge of how they are manufactured, how they are recognized by their intra- or extra-cellular targets, and their signals transduced under normal and pathological conditions. These molecules (natural or derived) are increasingly used as therapeutic agents and their structural and functional characterization opens the way to new pharmacopoeias. Our research aims to extend the repertoire of these molecules by understanding their mechanisms of biogenesis and their structure/function/activity relationships, using three themes related to the characterization of:

  • the aminopeptidase B (Ap-B). Ap-B is involved in proteolytic processing. It combines a specific aminopeptidase activity towards basic amino acids and a leukotriene A4 hydrolase (LTA4H) activity that hydrolyses the LTA4 into LTB4, a lipid mediator of inflammation.
  • peptide effectors involved in innate immunity, through the use of the remarkable property of the amphibian skin to secrete huge amounts of peptides that are identical or similar to those produced by tissues of mammals.
  • ecdysteroids, to clarify their pharmacological effects in mammals and humans. These molecules have anabolic, anti-obesity and anti-diabetic properties. Studies concern their metabolism and their mechanism of action via membrane receptors.

Highlights

Our work allowed to:

  • characterize the catalytic centre of Ap-B; identify its first physiological substrates in mammals (glucagon; cholecystokinin 9, CCK9); highlight the participation of the enzyme in the cytoplasmic maturation/degradation of MHC class I epitopes;
  • discover and characterize, in amphibians, the first examples of antimicrobial peptide (AMP) structured in alpha helix with an hydrophobic core and cationic ends (dermaseptin S9), of AMPs containing a glycine zipper motif (Plasticines), and novel Temporins. Isolated from the frog Pelophylax saharica, these temporins are small membranolytic AMPs (8-17 residues) active against multiresistant bacteria and parasites, but devoid of toxicity towards mammalian cells.
  • determine the bioavailability and metabolism of ingested ecdysteroids, specify their effects in an animal model of obesity, and identify the membrane receptor for these molecules.

Future directions

  • Aminopeptidase B. Identification of the physiological functions and catalytic mechanisms of the enzyme by: determination of the 3D structure, identification of amino acids involved in substrate recognition, catalysis and signalling pathways; identification of substrates in amphibians and mammals; design of specific inhibitors. The role of Ap-B in certain diseases (diabetes, inflammation, etc.) will also be addressed.
  • Antimicrobial peptides. Characterization of the mechanism of action and structure-activity relationship studies of temporins. The objective is to study the antiparasitic mode of action and to design pharmacomodulated peptides (stability, bioavailability and efficiency) to develop a new class of peptidic drugs that could be used in the fight against multiresistant bacteria, biofilms and parasites.
  • Ecdysteroids. Evaluation of their potential in the treatment of sarcopenia and sarcopenic obesity. The objective is to develop a method of prevention and/or treatment of these diseases in the context of collaboration with the Biophytis Institute.

Collaborations

• Prof. M. Beinfeld, Department of Pharmacology and Experimental Therapeutics, Tufts University, School of Medicine, Boston, MA, USA.

• Dr. G. Bolbach, Plate-forme Spectrométrie de Masse et Protéomique - IBPS, FR 3631, UPMC, Paris.

• Dr. J.-M. Cavaillon, Unité Cytokines & Inflammation, Institut Pasteur, Paris.

• Dr. J. Courty, J. Delbé, Laboratoire Croissance, Réparation et Régénération Tissulaires, EAC 7149 CNRS-Université Paris-Est, Créteil.

• Prof. C. Etchebest, Laboratoire de Bioinformatique Génomique et Moléculaire, Université Denis Diderot-Paris7, UMR S 726, INSERM, Paris.

• Pr. J.-P. Girault, Université Paris Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Paris.

• Dr V. Hook, Skaggs School of Pharmacy and Pharmaceutical Sciences and Depts. of Neuroscience, Pharmacology, and Medicine, University of California, San Diego, La Jolla, CA, USA.

• Dr. V. Humblot, M. Jaber, J. Landoulsi et C.-M. Pradier, Prof. J.-F. Lambert, Laboratoire de Réactivité de Surface, UMR 7197 UPMC/CNRS, UPMC, Paris.

• Prof. O. Lequin et S. Cribier, Dr. L. Khemtémourian et N. Rodriguez, Laboratoire des Biomolécules, UMR 7203, UPMC/CNRS, UPMC, Paris.

• Dr. N. Mamadalieva, Institute of the Chemistry of Plant Substances, Tashkent, Uzbekistan.

• Prof. D. O'Leary, Department of Chemistry, Pomona College, Claremont, USA.

• Dr. C. Piesse, Plate-forme d’Ingénierie des Protéines (Synthèse Peptidique - Interactions Biomoléculaires en Temps Réel) - IBPS, FR 3631, UPMC, Paris.

• Dr A. Quignard-Boulangé, Pr. D. Tomé, AgroParisTech, U914, Physiologie de la Nutrition et du Comportement Alimentaire, F-75005 Paris.

• Dr. S. Raynal, Metabrain Research, Chilly-Mazarin.

• Dr U. Seifert,Institut für Biochemie, Charité-Universitätsmedizin Berlin, CCM (Campus Charité Mitte), Berlin, Germany.

• Dr. D. Sereno et B. Oury, Equipe “Génétique et Biodiversité des Systèmes Infectieux” (GeneSys), UMR IRD 224-CNRS 5290-Université Montpellier 1 et 2, IRD, Montpellier.

• Dr. S. Veillet et W. Dioh, Institut Biophytis, Parc Biocitech, Romainville.

Publications

All the team's publications