Personne : Biron, Éric
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Université Laval. Faculté de pharmacie
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- PublicationAccès libreToward solid-phase peptide fragment ligation by a traceless-Ugi multicomponent reaction approach(Royal Society of Chemistry, 2016-11-14) Biron, Éric; Jobin, Steve; Galindo, Sindy-Marcela; Vézina-Dawod, Simon; Fontaine, Alexia; Liang, XinxiaA new methodology to couple peptide fragments on solid support using a traceless isocyanide-based multicomponent reaction is described. The approach uses a microwave-assisted on-resin Ugi four-component reaction to attach a carboxyl free peptide to a supported peptide bearing a free N-terminal amine via the formation of an N-protected amide bond at the ligation site. Afterward, the generated backbone amide protecting group can be efficiently removed by microwave-assisted acidolysis with trifluoroacetic acid to afford a fully deprotected peptide. This straightforward Ugi reaction/deprotection approach was applied to condense various fragment lengths and provided a variety of oligopeptides.
- 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.
- 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 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.
- PublicationRestreintLasso-inspired peptides with distinct antibacterial mechanisms(Springer-Verlag Wien, 2014-12-04) Biron, Éric; Gomaa, Ahmed; Fliss, Ismaïl; Bédard, François; Subirade, Muriel; Hammami, RiadhAbstract 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
- PublicationAccès libreN-Substituted arylsulfonamide building blocks as alternative submonomers for peptoid synthesis(Elsevier, 2015-01-08) Biron, Éric; Derson, Antoine; Vézina-Dawod, SimonPeptoids (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.
- PublicationRestreintPractical 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, XinxiaThe 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.
- PublicationRestreintA 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, FrançoisOne-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.
- PublicationAccès libreMachine learning assisted design of highly active peptides for drug discovery(Public Library of Science, 2015-04-07) Tremblay, Denise; Biron, Éric; Giguère, Sébastien; Moineau, Sylvain; Laviolette, François; Liang, Xinxia; Marchand, Mario; Corbeil, JacquesThe discovery of peptides possessing high biological activity is very challenging due to the enormous diversity for which only a minority have the desired properties. To lower cost and reduce the time to obtain promising peptides, machine learning approaches can greatly assist in the process and even partly replace expensive laboratory experiments by learning a predictor with existing data or with a smaller amount of data generation. Unfortunately, once the model is learned, selecting peptides having the greatest predicted bioactivity often requires a prohibitive amount of computational time. For this combinatorial problem, heuristics and stochastic optimization methods are not guaranteed to find adequate solutions. We focused on recent advances in kernel methods and machine learning to learn a predictive model with proven success. For this type of model, we propose an efficient algorithm based on graph theory, that is guaranteed to find the peptides for which the model predicts maximal bioactivity. We also present a second algorithm capable of sorting the peptides of maximal bioactivity. Extensive analyses demonstrate how these algorithms can be part of an iterative combinatorial chemistry procedure to speed up the discovery and the validation of peptide leads. Moreover, the proposed approach does not require the use of known ligands for the target protein since it can leverage recent multi-target machine learning predictors where ligands for similar targets can serve as initial training data. Finally, we validated the proposed approach in vitro with the discovery of new cationic antimicrobial peptides.
- PublicationRestreintCollagencin, an antibacterial peptide from fish collagen : activity, structure and interaction dynamics with membrane(Elsevier, 2016-03-30) Biron, Éric; Gomaa, Ahmed; Fliss, Ismaïl; Beaulieu, Lucie; Bédard, François; Subirade, Muriel; Ennaas, Nadia; Hammami, RiadhIn this study, we first report characterization of collagencin, an antimicrobial peptide identified from fish collagen hydrolysate. The peptide completely inhibited the growth of Staphylococcus aureus at 1.88 mM. Although non-toxic up to 470 μM, collagencin was hemolytic at higher concentrations. The secondary structure of collagencin was mainly composed by β-sheet and β-turn as determined by CD measurements and molecular dynamics. The peptide is likely to form β-sheet structure under hydrophobic environments and interacts with both anionic (phosphatidylglycerol) and zwitterionic (phosphoethanolamine and phosphatidylcholine) lipids as shown with CD spectroscopy and molecular dynamics. The peptide formed several hydrogen bonds with both POPG and POPE lipids and remained at membrane–water interface, suggesting that collagencin antibacterial action follows a carpet mechanism. Collagenous fish wastes could be processed by enzymatic hydrolysis and transformed into products of high value having functional or biological properties. Marine collagens are a promising source of antimicrobial peptides with new implications in food safety and human health.