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Biron, Éric

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Biron

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Éric

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Université Laval. Faculté de pharmacie

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ncf11849118

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Voici les éléments 1 - 10 sur 18
  • PublicationAccès libre
    Recent progress in the chemical synthesis of class II and s-glycosylated bacteriocins
    (Frontiers Research Foundation, 2018-05-23) Biron, Éric; Bédard, François
    A wide variety of antimicrobial peptides produced by lactic acid bacteria (LAB) have been identified and studied in the last decades. Known as bacteriocins, these ribosomally synthesized peptides inhibit the growth of a wide range of bacterial species through numerous mechanisms and show a great variety of spectrum of activity. With their great potential as antimicrobial additives and alternatives to traditional antibiotics in food preservation and handling, animal production and in veterinary and medical medicine, the demand for bacteriocins is rapidly increasing. Bacteriocins are most often produced by fermentation but, in several cases, the low isolated yields and difficulties associated with their purification seriously limit their use on a large scale. Chemical synthesis has been proposed for their production and recent advances in peptide synthesis methodologies have allowed the preparation of several bacteriocins. Moreover, the significant cost reduction for peptide synthesis reagents and building blocks has made chemical synthesis of bacteriocins more attractive and competitive. From a protein engineering point of view, the chemical approach offers many advantages such as the possibility to rapidly perform amino acid substitution, use unnatural or modified residues, and make backbone and side chain modifications to improve potency, modify the activity spectrum or increase the stability of the targeted bacteriocin. This review summarized synthetic approaches that have been developed and used in recent years to allow the preparation of class IIa bacteriocins and S-linked glycopeptides from LAB. Synthetic strategies such as the use of pseudoprolines, backbone protecting groups, microwave irradiations, selective disulfide bridge formation and chemical ligations to prepare class II and S-glycosylsated bacteriocins are discussed.
  • PublicationAccès libre
    Convenient two-step synthesis of highly functionalized benzo-fused 1,4-diazepin-3-ones and 1,5-diazocin-4-ones by sequential Ugi and intramolecular SNAr reactions
    (Pergamon Press, 2017-09-18) Biron, Éric; Vézina-Dawod, Simon; Liang, Xinxia; Gerber, Nicolas
    Benzodiazepinones are an important family of heterocycles with very attractive pharmacological properties and peptidomimetic abilities. We report herein a rapid and efficient two-step synthesis of polysubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones using a multicomponent condensation/cyclization strategy. The approach uses an Ugi four-component reaction to condense readily available Nα-Fmoc-amino acids, amines and isocyanides with a 2-fluorobenzaldehyde derivative followed by a one-pot Fmoc-group removal, intramolecular aromatic nucleophilic substitution for ring closure and side chain deprotection. The described method gives access to benzo-fused 7- and 8-membered rings bearing a wide variety of functionalized substituents and was applied to efficiently prepare tri- and tetrasubstituted 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones in high yields in two straightforward steps.
  • PublicationAccès libre
    Synthesis, antimicrobial activity and conformational analysis of the class IIa bacteriocin pediocin PA-1 and analogs thereof
    (Springer Nature, 2018-06-13) Biron, Éric; Fliss, Ismaïl; Bédard, François; Rebuffat, Sylvie; Menétrey, Séverine; Hammami, Riadh
    The antimicrobial peptide pediocin PA-1 is a class IIa bacteriocin that inhibits several clinically relevant pathogens including Listeria spp. Here we report the synthesis and characterization of whole pediocin PA-1 and novel analogs thereof using a combination of solid- and solution-phase strategies to overcome difficulties due to instability and undesired reactions. Pediocin PA-1 thus synthesized was a potent inhibitor of Listeria monocytogenes (MIC = 6.8 nM), similar to the bacteriocin produced naturally by Pediococcus acidilactici. Of particular interest is that linear analogs lacking both of the disulfide bridges characterizing pediocin PA-1 were as potent. One linear analog was also a strong inhibitor of Clostridium perfringens, another important food-borne pathogen. These results are discussed in light of conformational information derived from circular dichroism, solution NMR spectroscopy and structure-activity relationship studies.
  • PublicationAccès libre
    The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system
    (American Society for Clinical Investigation, 2019-04-02) Bouyakdan, Khalil; Biron, Éric; Martin, Hugo; Liénard, Fabienne; Budry, Lionel; Taib, Bouchra; Rodaros, Demetra; Chrétien, Chloé; Husson, Zoé; Cota, Daniela; Pénicaud, Luc; Fulton, Stephanie; Fioramonti, Xavier; Alquier, Thierry
    Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA–binding protein–derived (ACBP-derived) endozepines are secreted peptides that modulate the GABAA receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes, and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP+ astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. ACBP+ astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons, and ODN selectively activated POMC neurons through the ODN GPCR but not GABAA, and suppressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system.
  • PublicationRestreint
    Synthetic Strategies for Macrocyclic Peptides
    (John Wiley & Sons, 2017-08-18) Biron, Éric; Vézina-Dawod, Simon; Bédard, François
    Peptide macrocycles form an outstanding class of natural and synthetic bioactive compounds. This chapter discusses synthetic strategies for the final ring‐closing reaction by the widely employed and versatile processes of lactamization, lactonization, and disulfide bridge formation. According to the nature of the chemical bond found in the backbone, cyclic peptides can be classified in two major categories: homodetic peptides and heterodetic peptides. In principle, all methods suitable for peptide bond formation can be applied for head‐to‐tail macrocyclization of linear peptides; however the reaction usually proceeds more slowly than the corresponding bimolecular version. During synthesis design, the C‐terminal amino acid of the linear precursor and the coupling reagent should be carefully chosen to minimize epimerization at the C‐terminal residue during cyclization. In many cases, the solution‐phase strategy is the best choice for performing the macrocyclization step, especially when larger quantities of cyclic peptide are required.
  • PublicationRestreint
    Development of a solid-phase traceless-Ugi multicomponent reaction for backbone anchoring and cyclic peptide synthesis
    (Wiley, 2018-02-13) Biron, Éric; Jobin, Steve; Beaumont, Catherine
    A new one-pot methodology to anchor peptides by their backbone to a solid support using an isocyanide-based multicomponent reaction is described. The approach uses a microwave-assisted Ugi four-component reaction to simultaneously condense and bind an N-protected amino acid and an amino ester to a supported aldehyde. Afterward, the generated backbone anchored dipeptide can be used in solid-phase peptide synthesis to prepare head-to-tail cyclic peptides. Moreover, we also show that peptide fragment ligation can be performed with the described one-pot anchoring. The backbone anchored peptides can be efficiently released from the resin by microwave-assisted acidolysis with trifluoroacetic acid. This straightforward one-pot anchoring approach was also applied to condense fragments and prepare a variety of linear and macrocyclic peptides.
  • PublicationRestreint
    A convenient approach to prepare topologically segregated bilayer beads for one-bead two-compound combinatorial peptide libraries
    (Springer, 2012-07-18) Girard, Anick; Biron, Éric; Bédard, François
    One-bead one-compound (OBOC) combinatorial peptide libraries have been used to identify ligands and modulators for a wide variety of biological targets. While being very efficient with linear peptides, OBOC libraries with N-terminally blocked peptides or with unsequenceable building blocks require encoding. To fully exploit OBOC combinatorial methods with cyclic peptides and peptidomimetics, topologically segregated bilayer beads have been developed. This strategy offers the opportunity to synthesize two compounds per bead, i.e. with one compound exposed on the bead surface for screening, and the other one found within the inner layer as a tag for sequencing and compound identification. Bead segregation often involves the use of unstable derivatives or requires a series of protection–deprotection steps. In order to expedite and optimize bead segregation, the performance of various reagents has been studied. The results obtained herein show that bead segregation can be efficiently performed with commercially available reagents. Finally, in order to control outer/inner layer ratios in segregated beads, the effects of different parameters have been evaluated. We report a straightforward and efficient procedure to prepare topologically segregated bilayer beads in a wide range of controllable, predictable, and reproducible outer versus inner ratios.
  • PublicationRestreint
    Practical ring-opening strategy for the sequence determination of cyclic peptides from one-bead-one-compound libraries
    (American Chemical Society, 2013-09-26) Girard, Anick; Biron, Éric; Liang, Xinxia
    The use of cyclic peptides in one-bead-one-compound libraries is limited by difficulties in sequencing hit compounds. Lacking a free N-terminal amine, such peptides cannot be sequenced by the Edman degradation approach, and complex fragmentation patterns are obtained by tandem mass spectrometry. To overcome this problem, we designed an alternative approach introducing a methionine residue within the macrocycle and as a linker to allow simultaneous ring-opening and release from the resin upon treatment with cyanogen bromide. The methionine linker was inverted relative to the peptide chain to allow the synthesis of cyclic peptides anchored by a lysine side chain and to avoid the presence of two C-terminal homoserine lactones on the released linear peptides. After MALDI-TOF MS/MS analysis, the peptides released from a single bead were sequenced manually and with a de novo sequencing software. The strategy described herein is compatible with commonly used amino acids and allows sequencing of cyclic peptides in one-bead-one-compound libraries, thus reducing the need for encoding.
  • PublicationAccès libre
    N-Substituted arylsulfonamide building blocks as alternative submonomers for peptoid synthesis
    (Elsevier, 2015-01-08) Biron, Éric; Derson, Antoine; Vézina-Dawod, Simon
    Peptoids (oligo N-substituted glycines) are peptidomimetic oligomers showing attractive structural and pharmacological properties. The efficiency of their synthesis has prompted the use of peptoids in combinatorial libraries. To increase the chemical diversity accessible in peptoid design and libraries, we demonstrate here that N-substituted o-nitrobenzenesulfonamide derivatives can be used as alternative building blocks in the synthesis of peptoids by the submonomer approach. The preparation of N,O-protected amino alcohol submonomers and the conditions for their incorporation into peptoid oligomers are reported. The described method is compatible with the submonomer approach and was applied to prepare peptoid oligomers bearing different hydroxylated side chains.
  • PublicationRestreint
    Lasso-inspired peptides with distinct antibacterial mechanisms
    (Springer-Verlag Wien, 2014-12-04) Biron, Éric; Gomaa, Ahmed; Fliss, Ismaïl; Bédard, François; Subirade, Muriel; Hammami, Riadh
    Abstract Microcin J25 (MccJ25) is an antibacterial peptide with a peculiar molecular structure consisting of 21 amino acids and a unique lasso topology that makes it highly stable. We synthesized various MccJ25-derived peptides that retained some of the inhibitory activity of the native molecule against Salmonella enterica and Escherichia coli. Of the tested peptides, C1, 7-21C and WK_7-21 were the most inhibitory peptides (MIC = 1–250 µM), but all three were less potent than MccJ25. While MccJ25 was not active against Gram-positive bacteria, the three derived peptides were slightly inhibitory to Gram-positive bacteria (MIC = 250 µM). At 5 µM, C1, 7-21C and WK_7-21 reduced E. coli RNA polymerase activity by respectively, 23.4, 37.4 and 65.0 %. The MccJ25 and its derived peptides all appeared to affect the respiratory apparatus of S. enterica. Based on circular dichroism and FTIR spectroscopy, the peptides also interact with bacterial membrane phospholipids. These results suggest the possibility of producing potent MccJ25-derived peptides lacking the lasso structure. Keywords Antimicrobial peptides · Microcin J25 · Solid phase peptide synthesis · Antibacterial activity · Mode of action