Personne : Biron, Éric
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Université Laval. Faculté de pharmacie
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- PublicationRestreintCross-reactivity to cephalosporins and carbapenems in penicillin-allergic patients : two systematic reviews and meta-analyses(Elsevier, 2019-06-04) Picard, Matthieu; Biron, Éric; Robitaille, Geneviève; Daigle, Jean-Marc; Karam, Fatiha; Bédard, François; Tardif, Mélanie; Lacombe-Barrios, Jonathan; Bégin, PhilippeBACKGROUND: There is no recent systematic review on therisk of cross-reactivity to cephalosporins and carbapenems inpenicillin-allergic patients despite many new studies on the subject. All past reviews have several limitations such as not including any patient with a T-celle mediated penicillin allergy. OBJECTIVES: To determine the risk of cross-reactivity to cephalosporins and carbapenems in patients with a proven IgE-or T-cellemediated penicillin allergy. To measure the association between R1 side chain similarity on cephalosporins andpenicillins and the risk of cross-reactivity. METHODS: MEDLINE and EMBASE were searched fromJanuary 1980 to March 2019. Studies had to include at least 10 penicillin-allergic subjects whose allergy had been confirmed bya positive skin test (ST) or drug provocation test (DPT) result.Cross-reactivity had to be assessed to at least 1 cephalosporin orcarbapenem through ST or DPT. Both random-effects andfixed-effect models were used to combine data. A bioinformaticmodel was used to quantify the similarity between R1 sidechains. RESULTS: Twenty-one observational studies on cephalosporincross-reactivity involving 1269 penicillin-allergic patientsshowed that the risk of cross-reactivity varied with the degree ofsimilarity between R1 side chains: 16.45% (95% CI, 11.07-23.75) for aminocephalosporins, which share an identical sidechain with a penicillin (similarity score[1), 5.60% (95% CI,3.46-8.95) for a few cephalosporins with an intermediate simi-larity score (range, 0.563-0.714), and 2.11% (95% CI, 0.98-4.46) for all those with low similarity scores (below 0.4), irre-spective of cephalosporin generation. The higher risk associatedwith aminocephalosporins was observed whether penicillin al-lergy was IgE- or T-cellemediated. Eleven observational studieson carbapenem cross-reactivity involving 1127 penicillin-allergicpatients showed that the risk of cross-reactivity to any carba-penem was 0.87% (95% CI, 0.32-2.32). CONCLUSIONS: Although it remains possible that these meta-analyses overestimated the risk of cross-reactivity, cliniciansshould consider the increased risk of cross-reactivity associatedwith aminocephalosporins, and to a lesser extent withintermediate-similarity-score cephalosporins, compared with thevery low risk associated with low-similarity-score cephalosporinsand all carbapenems when using beta-lactams in patients with asuspected or proven penicillin allergy.
- PublicationAccès libreStructure-activity studies of the bacteriocin bactofencin A and its interaction with the bacterial membrane(American Chemical Society, 2018-12-12) Biron, Éric; Fliss, Ismaïl; Bédard, FrançoisThe antimicrobial peptide bactofencin A is an unmodified non-pediocin-like bacteriocin that inhibits several clinically relevant pathogens, including Listeria monocytogenes and Staphylococcus aureus. Here we report the synthesis and structure–activity relationship studies of bactofencin A and novel analogues thereof. Synthetic bactofencin A was a potent inhibitor of L. monocytogenes (MIC = 8.0 μM) and S. aureus (MIC = 4.0 μM), similar to the bacteriocin produced naturally by Lactobacillus salivarius. Of particular interest is the fact that linear analogues lacking the disulfide bond found in bactofencin A were as potent and also active against several strains of methicillin-resistant S. aureus (MRSA) and one strain of vancomycin-resistant S. aureus (VRSA). Supported by the structure–activity relationship study, investigation of the interaction of bactofencin A with bacterial membrane by molecular dynamics simulations showed the importance of the positively charged N-terminal tail for peptide–membrane interaction. These results suggest that the C-terminal macrocycle is involved in target protein binding and bacterial growth inhibition.
- PublicationRestreintDevelopment of a solid-phase traceless-Ugi multicomponent reaction for backbone anchoring and cyclic peptide synthesis(Wiley, 2018-02-13) Biron, Éric; Jobin, Steve; Beaumont, CatherineA 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.
- PublicationAccès libreIn vitro assessment of skin sensitization, irritability and toxicity of bacteriocins and reuterin for possible topical applications(Nature Publishing Group, 2022-03-17) Biron, Éric; Frédéric Couture; Soltani, Samira; Fliss, Ismaïl; Subirade, Muriel; Boutin, Yvan.Bacteriocins and reuterin are promising antimicrobials for application in food, veterinary, and medical sectors. In the light of their high potential for application in hand sanitizer, we investigated the skin toxicity of reuterin, microcin J25, pediocin PA-1, bactofencin A, and nisin Z in vitro using neutral red and LDH release assays on NHEK cells. We determined their skin sensitization potential using the human cell line activation test (h-CLAT). Their skin irritation potential was measured on human epidermal model EpiDerm™. We showed that the viability and membrane integrity of NHEK cells remained unaltered after exposure to bacteriocins and reuterin at concentrations up to 400 µg/mL and 80 mg/mL, respectively. Furthermore, microcin J25 and reuterin showed no skin sensitization at concentrations up to 100 µg/mL and 40 mg/mL, respectively, while pediocin PA-1, bactofencin A, and nisin Z caused sensitization at concentrations higher than 100 µg/mL. Tissue viability was unafected in presence of bacteriocins and reuterin at concentrations up to 200 µg/mL and 40 mg/ mL, respectively, which was confrmed by measuring cytokine IL-1α and IL-8 levels and by histological analysis. In conclusion, the current study provides scientifc evidence that some bacteriocins and reuterin, could be safely applied topically as sanitizers at recommended concentrations
- PublicationAccès libreThe 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, ThierryGlial 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.
- PublicationAccès libreGastrointestinal stability and cytotoxicity of bacteriocins from gram-positive and gram-negative bacteria : a comparative in vitro study(Frontiers Media, 2022-01-25) Biron, Éric; Zirah, Séverine; Rebuffat, Sylvie; Soltani, Samira; Couture, Frédéric; Fliss, Ismaïl; Subirade, Muriel; Boutin, Yvan.Bacteriocins are receiving increased attention as potent candidates in food preservation and medicine. Although the inhibitory activity of bacteriocins has been studied widely, little is known about their gastrointestinal stability and toxicity toward normal human cell lines. The aim of this study was to evaluate the gastrointestinal stability and activity of microcin J25, pediocin PA-1, bactofencin A and nisin using in vitro models. In addition cytotoxicity and hemolytic activity of these bacteriocins were investigated on human epithelial colorectal adenocarcinoma cells (Caco-2) and rat erythrocytes, respectively. Pediocin PA-1, bactofencin A, and nisin were observed to lose their stability while passing through the gastrointestinal tract, while microcin J25 is only partially degraded. Besides, selected bacteriocins were not toxic to Caco-2 cells, and integrity of cell membrane was observed to remain unaffected in presence of these bacteriocins at concentrations up to 400 μg/mL. In hemolysis study, pediocin PA-1, bactofencin A, and nisin were observed to lyse rat erythrocytes at concentrations higher than 50 μg/mL, while microcin J25 showed no effect on these cells. According to data indicating gastrointestinal degradation and the absence of toxicity of pediocin PA-1, bactofencin A, and microcin J25 they could potentially be used in food or clinical applications.
- PublicationRestreintSynthetic Strategies for Macrocyclic Peptides(John Wiley & Sons, 2017-08-18) Biron, Éric; Vézina-Dawod, Simon; Bédard, FrançoisPeptide 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.
- PublicationAccès libreRecent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer(Pergamon Press, 2015-07-18) Biron, Éric; Bédard, FrançoisThe androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favourable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.
- PublicationAccès libreOne-pot photochemical ring-opening/cleavage approach for the synthesis and decoding of cyclic peptide libraries(American Chemical Society, 2016-02-25) Biron, Éric; Porte, Karine; Vézina-Dawod, Simon; Bédard, François; Liang, XinxiaA novel dual ring-opening/cleavage strategy to determine the sequence of cyclic peptides from one bead, one compound libraries is described. The approach uses a photolabile residue within the macrocycle and as a linker to allow a simultaneous ring opening and cleavage from the beads upon UV irradiation and provide linearized molecules. Cyclic peptides of five to nine residues were synthesized and the generated linear peptides successfully sequenced by tandem mass spectrometry.
- PublicationAccès librePreparation of N-substituted N-arylsulfonylglycines and their use in peptoid synthesis(American Chemical Society, 2015-11-09) Biron, Éric; Jobin, Steve; Herby, Claire; Vézina-Dawod, Simon; Derson, AntoineTo increase the chemical diversity accessible with peptoids and peptide–peptoid hybrids, N-alkylated arylsulfonamides were used to prepare side chain protected N-substituted glycines compatible with solid-phase synthesis. The described procedures give access to peptoid monomers bearing a wide variety of functional groups from commercially available amines in four straightforward steps. The prepared N-substituted N-arylsulfonylglycines were used as monomers in solid-phase synthesis to introduce relevant functionalized side chains into peptoid oligomers and peptide–peptoid hybrids.