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phosphate buffer (IGP) and was nothemolytic in phosphate buffered saline(PBS).The amidated fluorescently labeledanalogues Fluo-Shep Ia, Fluo-Shep I (3-28)a and Fluo-Shep I (6-28)a were (i)more active against C. albicans ATCC90028 than their respective unlabeledanaloguesand (ii) rapidly internalizedinto C. albicans in an energy-andtemperature-dependent manner (Figure 2)that suggest internalization by endocyticprocess.Except for the [Trp 3 ]-Shep I (3-28)aanalogue, all amidated Trp-containinganalogues were 2-fold more active thanShep Ia against C. albicans ATCC90028. All of them were equally or 2-fold less active than Shep Ia against C.parapsilosis ATCC 22019 and equally or2-fold more active against C. kruseiATCC 6258. None of them washemolytic in IGP or PBS.Altogether, these results indicatethat: (i) amidated Trp-containingFig. 2. Effect of the temperature and sodiumazide (NaN 3 ) on internalization ofFluo-Shep Ia (insert of C). (A) control, (B)0.05% NaN 3 at 37°C, (C) 37°C and (D)0°C.analogues of Shep I can act as anticandidal drugs; (ii) [Trp 6 ]-Shep I (6-28)a is the bestanalogue obtained so far; (iii) the fluorescently labeled analogues have the potential to actas vectors for the delivery of macromolecules and/or drugs into cells.Table 1. Effect of the Zn 2+ ion on the MICs (µM) of Shep I and some analoguesPeptideC. albicansMDM8C. albicansATCC 90028C. albicansHU 168C. tropicalisSquibb 1600No Zn 2+ Zn 2+ No Zn 2+ Zn 2+ No Zn 2+ Zn 2+ No Zn 2+ Zn 2+Shep I 12.5 3.13 >100 >100 25 6.25 1.56 n.d.Shep Ia 12.5 1.56 >100 6.25 25 3.13 1.56 0.39Shep I (3-28)a 12.5 3.13 >100 25 25 6.25 1.56 1.56Shep I (6-28)a 12.5 3.13 >100 >100 50 12.5 1.56 1.56AcknowledgmentsSupported by grant 2008/11695-1 (FAPESP) and 142022/2003-9 (CNPq/doctoral fellowship for CR).We thank Dr. N. Lincopan (C. albicans ATCC 90028 and HU 168 strains), Dr. S.R. Almeida(C. krusei ATCC 6258 and C. parapsilosis ATCC 22019), A.Y. Matzukuma and R.C. Modia (helpwith FACS and confocal microscopy, respectively).References1. Planta, M.D. J. Am. Board Fam. Med. 20, 533-539 (2007).2. Park, C.J., et al. Plant Mol. Biol. 44, 187-197 (2000).3. Remuzgo, C., et al. Biopolymers 92, 65-75 (2009).4. Souza, M.P., et al. Tetrahedron 60, 4671-4681 (2004).5. Fehlbaum, P., et al. J. Biol. Chem. 269, 33159-33163 (1994).6. Machado, A., et al. Biopolymers 88, 413-426 (2007).415
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Targeting the Nuclear Pore Complex with Proteomimetic CellPenetrating PeptidesSarah Jones and John HowlResearch Institute in Healthcare Science, University of Wolverhampton,Wolverhampton, WV1 1LY, UKIntroductionThe past decade has witnessed a resurgent interest in the therapeutic utilizations of cellpenetrating peptides (CPPs). Accordingly, CPP technologies have successfully beenemployed for the modulation of intracellular signal transduction. Moreover, CPPs withintrinsic signal transduction modulatory properties offer a novel strategy for the modulationof intracellular biological events [1-3]. QSAR analysis was employed to identify putativeCPP sequences within human Cytochrome c [4]. Two such sequences located within the C-terminal helix, Cyt c 77-101 and Cyt c 86-101 induced apoptosis of malignant astrocytoma whenexogenously applied, thus mimicking the well-documented role(s) of Cyt c as a keyregulator of programmed cell death [1]. Whilst Cyt c 86-101 preferentially demonstrated anuclear localization [1], Cyt c 77-101 proved to be an extremely efficient CPP and was thusselected for modification to incorporate additional bioactive peptide sequences.Results and DiscussionN-terminal extension of Cyt c 77-101 , via a flexible aminohexanoic acid linker, with a targetmimetic of FxFG nucleoporins (Nup153 980-987 , CH 3 CO-NFKFGLSS) yielded a chimericpeptide (Ac-Nup153-Cyt c) that displayed a significantly enhanced apoptogenic potency(LD 50 = 0.73 μM) compared to Cyt c 77-101 alone and a scrambled chimeric analogue,(Ac-ScrNup153-Cyt c) (Table 1). Significantly, the apoptogenic potency of Ac-Nup153-Cytc (0.73 μM) would also indicate in vivo applicability. The detection of intra-nucleosomalDNA fragmentation by in situ TUNEL analysis and a specific activation of caspase-3confirmed that apoptosis was indeed the mechanism of cell death employed by Ac-Nup153-Cyt c in the U373MG astrocytoma model cell line.To gain insight into the possible mechanisms employed by this novel chimericconstruct, Nup153 980-987 was translocated into U373MG cells as a fluorescein-labelleddisulphide-linked cargo, using the inert CPP M918. Following a subsequent intracellularreduction of cysteine, liberated Fluo-Nup153 980-987 assumed a preferential co-localizationwith the nuclear pore complex (NPC). To refine these results, U373MG cells were treatedwith the rhodamine-labelled chimera Rho-Nup153-Cyt c (3 M) and scrambled analoguefor 1 hour. Whilst the scrambled chimera demonstrated a diffuse and generalisedcytoplasmic distribution, Rho-Nup153-Cyt c strongly co-localised with the nuclear poreprotein nucleoporin 153 (Table 1). Moreover, after 4 hours of treatment, exogenousapplication of Ac-Nup153-Cyt c (3 M) further facilitated the dramatic redistribution ofimmuno-labelled NPC proteins into the nucleoplasm and cytoplasm, a phenomenon thatwas not a downstream consequence of caspase activation since this redistribution event alsooccurred in the presence of the pan-caspase inhibitor Q-VD-Oph (20 M).Studies with scrambled peptides confirmed that the observed apotogenic action wasboth translocation- and sequence-dependent. Notably, translocation efficacies of bothchimeras, Rho-Nup153-Cyt c and Rho-ScrNup153-Cyt c, were significantly enhanced(408.5 + 15.8 fold and 412.5 + 5.20 fold, respectively) compared to that of Cyt c 77-101 alone(105.9 + 0.42 fold) and thus indicates a sequence-dependent specificity of action for theAc-Nup153-Cyt c chimera. We conclude that Ac-Nup153-Cyt c demonstrates therapeuticpotential as a potent inducer of apoptosis, whilst propounding the nuclear pore complex asan accessible, and therefore druggable, intracellular target.416
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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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