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Coupling was done by the TBTU method.The final step of the synthesis of PNAanalogues was cleavage from the resin.SPPS was performed bothconventionally and by using microwaveirradiation (MARS-X). Some of the steps ofSPPS were performed using bothtechniques. One of the reasons for usingMWA-SPPS was the shorter reaction time.It was several times shorter thanconventional SPPS. And because of theshorter time the possibility for racemizationis less pronounced. For instance, thesynthesis of (NCan) 3 pseudopeptidebackbone by conventional SPPS took about11 hours, but in MWA-SPPS the time wasabout 1 hour and 15 minutes. Even in thesecond case not all steps of the scheme wereperformed in conditions of microwaveirradiation. The process could be optimizedto be faster and to prevent racemization ofunnatural amino acid analogues.Our purpose was to synthesize chiralPNA oligonucleotide analogues and wemonitored their purity at each step of thesynthetic scheme.In conclusion we could say that newclasses of chiral PNAs were synthesized.Synthesis was made by both conventionaland microwave-assisted methods. Reactiontime is many times shorter in microwaveassistedsynthesis than in conventionalsynthesis.AcknowledgmentsWe are grateful to the European Social Fund andthe Bulgarian Ministry of Education and Science(Contract BG051РО001-3.3.04/58 – 2009) andNFSR of Bulgaria (Contract MY-FS-13-07).References1. Dzimbova, T., Pajpanova, T., Golovinsky, E.Collect. Czech. Chem. Commun. 6, 12-14 (2003).2. Dzimbova, T., Pajpanova, T., Tabacova, S.,Golovinsky, E. In: 5th Hellenic Forum onBioactive Peptides, TYPORAMA, Greece,Cordopatis P. (Ed.), 223-227(2007).3. Nielsen, P.E., Egholm, M., Berg, R.H., Buchardt,O. Science 254, 1497-1500 (1991).4. Dueholm, K.L., Egholm, M., Behrens, C.,Christensen, L., Hansen, H.F., Vulpius, T.,Petersen, K.H., Berg, R.H., Nielsen, P.E,Buchardt, O. J. Org. Chem. 59, 5767-5773(1994).BocFmocNHXCOOHFmocBocFmocFmocCs 2 CO 3NHXXBocNHCOCOn *NH 2X COn *TCH 2 CONHFmoc X COn *TCH 2 CONHH X COMerrifieldresinCoupling reaction steps(SPPS Protocols)10% TFA10 minTCH 2 COOHCleavage of thePNA analoguefrom the resinOHnX = CH 2 CH 2 CH 2 CH 2 NHCH 2 SO 2 NHCH 2 CH 2 NHCH 2 SO 2 NHC(NH)NHCH 2 ONHCH 2 ONHC(NH)NHFig. 3. Scheme of PNA synthesis.Figure 3. Scheme of PNA synthesis235
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010A New Synthetic Strategy for Novel AntibacterialHybrid Drug-Like MoleculesI. Lapidot 1,2 , G. Zats 1,2 , A. Albeck 2 , G. Gellerman 1 , and S. Shatzmiller 11 Department of Biological Chemistry, Ariel, 40700, Ariel University Center of Samaria,Israel; 2 Department of Chemistry, Ramat-Gan, 52900, Bar-Ilan University, IsraelIntroductionThe phenomenon of antibiotic resistant bacteria is a global problem which is hard to dealwith and is getting worse. Therefore, it is necessary to discover new antibiotics.Antibacterial peptides (AMPs) are the effector molecules of innate immunity. Generallythey contain 15–45 amino acid residues. Most antibacterial peptides share several commonfeatures i.e.: positive charge domains (i.e. contain lysines and arginines), hydrophobicamino acids (i.e. contain valine and phenyl alanine) and amphipathic structures.Furthermore, most native antimicrobial peptides have no cytolytic activity against normalmammalian cells at their minimal antimicrobial inhibitory concentration (MIC) [1].Various known and novel scaffolds are, among others, 1, 4-Dihydropyridines [2,3] andBenzodiazepines [4,5]. They are abundant source of molecules with proven biologicalactivity. The present research refers to the phenomenon of pharmacokinetics as well aspharmacodynamics in pharmacologic activity, namely the modification that extends use ofexisting medicines. In particular, the changes of the medications which are known andusable. For medicines known, this change is achieved by combining them with peptidesequences (based on Dermaseptine fragments [6,7]), in order to produce hybrid drug likemolecules with better desired potential therapeutic features.Results and DiscussionThe advantage of the AMPs over conventional antibiotics is their operating mechanism,which refers to the interaction between the bacteria's membrane and the peptide. This factmakes it much more difficult for the microorganisms to develop resistancy to AMPs.Bacteria’s ability to become resistant to antibiotics presents an urgent need to developvarious tools to supplement the current available antibiotic treatments. However, thepharmaceutical industry shows interest in Synthetic Antimicrobial Peptidomimetics(SAMPs) and not in AMPs. The reason for that preference is probably because of the highmolecular weight of the natural polypeptides, low stability in the blood serum, lowselectivity and the high cost [8,9].We have identified in the amino-acids sequence of the antibacterial polypeptide fromfrog skins, Dermaseptin-S1 (Figure 1) a short sequence of 5 amino-acids (via the Linearepitope system) present in the natural product, namely KTMLK ([1a] Lys-Thr-Met-Leu-Lys). This was found to have bactericidal activity, i.e. killing Gram negative as well asGram positive bacteria. Linear epitopes based on [1a] were prepared in which the aminoacidsT and M as well as L were replaced by other hydrophobic amino acids. All show thesame biological activity.S4=ALLGAAADTISQGTQWMTLLKKVLKAAAKALNAVLVGANAS1=ALWKTMLKKLGTMALHAGKAAFig. 1. Dermaseptine sequence amino-acids (S1 & S4).As a result of all these facts we designed novel peptidomimetics compounds that contain1,4-Dihydropyridines (IL) and Benzodiazepines (GZ) (scaffolds- Figure 2) bound to AMPssequence that derived from the Dermaseptine skin – all this unit together constitute Hybriddrug-like molecule.There are many suggestions for mechanisms explaining the bactericidal nature of thesemore than 800 isolated natural antimicrobial peptides [8-10]. However, one of thesemechanisms is based on the idea that positively charged amino acids like Lysine, Argininepresent in the antimicrobial peptides in large abundance can replace metal cations attachedto phospholipids – lipopolysacchrides [11] and peptide-glycans – Teichoic acid [12] layersforming the essential supra-molecular structures based on coordination with metal cations236
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Peptides 2010Tales of PeptidesProce
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Peptides 2010Tales of PeptidesProce
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IntroductionWe had the distinct hon
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Scientific programIn planning the 3
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31 st EUROPEAN PEPTIDE SYMPOSIUMSep
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published by John Wiley & Sons as a
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The Josef Rudinger AwardThis award
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Young Investigators' SymposiumThe y
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xxiv
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Design of Peptidyl-Inhibitors for G
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Synthetic Antifreeze Glycopeptide A
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Synthesis and Oxidative Folding of
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Convergent Syntheses of Huprp106-12
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Bactericidal Activity of Small Beta
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Bradykinin Analogues Acylated on Th
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Antimicrobial Activity of Small 3-(
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Interaction of Curcumin with A-Synu
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Fluorescent and Luminescent Fusion
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Cellular Expression of the Human An
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2D IR Spectroscopy of Oligopeptides
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large, non-redundant subset of prot
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The aberrantly glucosylated peptide
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Table 1. Proline cis/trans ratios o
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Table 1. Yields, UV-vis absorption
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Table 1. Purity of the targeted tri
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processes are blocked. Interestingl
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(tb4 n ,1 m )MTII(tb1 n ,4 m )MTIIF
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Fig. 2. a) Part of the 400 MHz HR-M
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Once printed, the amino acid partic
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A) PSA, few seconds73B) PSA, 45 min
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short β strands. In contrast, nume
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neg. control Cs9-Rhd MM-218Fig. 2.
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Table 1. The general structure of t
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% ID in the liver 1 h p.i.100908070
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Peptidyl phosphoranes were first re
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obtained from the same sardines and
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MccJ25 variants were produced by si
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Fig. 2. Proposed signaling mechanis
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Table 1. mCD4-HS12 antiviral activi
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Subject index(S)-2-(1-adamantyl)gly
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chip 18chiral triazine condensing r
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heat stress 348helical conformation
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O-acyl isopeptide method 112obesity
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SH2-ligands 210short collagen-relat
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Author indexAboye, Teshome Leta 142
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Chi, Hongfang 480Chiche, Laurent 6C
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Geronikaki, Athina 444Gessmann, Ren
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Kostova, Kalina 528Kotzia, Georgia
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Nagata, Koji 162Nagayev, Igor Yu. 5
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Salvarese, Nicola 518Sammet, Benedi
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Vauquelin, Georges 138Veiga, Ana Sa
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