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The GnRH-III based bioconjugates with or without spacer (GnRH-III(Dau=Aoa-GFLG),GnRH-III(Dau=Aoa-YRRL) and GnRH-III(Dau=Aoa)) showed similar cytostatic effectthat was higher on MCF-7 cells (IC 50 : 1-5 μM) than on HT-29 cells (IC 50 : 10-30 μM)(Table 1). Because the stability of the YRRL spacer was fairly low in human serum, onlythe other two compounds were tested in vivo. The in vivo antitumor activity was evaluatedon HT-29 human colon carcinoma bearing SCID mice. GnRH-III(Dau=Aoa) and GnRH-III(Dau=Aoa-GFLG) bioconjugates injected 3 times at a dose of 15 mg/kg Dau content hadsignificant antitumor activity (tumor growth inhibition: 41% and 50%, respectively on theday 35 after tumor transplantation) (Figure 2). Mice treated with free Dau, 5 mg/kg or 2.5mg/kg body weight, died before the second treatment (till the day 20 or 23, respectively).Table 1. In vitro long term antitumor activity of Dau-GnRH derivative bioconjugatesCompoundsHT-29MCF-7(IC 50 /µM)(IC 50 /µM)Daunorubicin-HCI 2.5 ±1.1 0.23 ±0.03GnRH-III >100 >100GnRH-III(GFLG) >100 >100GnRH-III(Dau=Aoa) 14.2± 3.2 2.2 ±1.2GnRH-III(Dau=Aoa-GFLG) 19.4± 3.1 3.9 ±1.2GnRH-III(Dau=Aoa-YRRL) 28.6 ±5.5 1.8 ±0.5MI-1892 >100 >100MI-1892(Dau=Aoa) 16.1± 1.9 7.4 ±0.5MI-1892[ 5 Lys](Dau=Aoa) 3.8 ±0.1 1.0 ±0.3MI-1892(Dau=Aoa-YRRL) 16.2 ±2.0 6.9 ±1.5A3.0controlB3.0Tumor volume (cm 3 )2.52.01.51.00.5GnRH-III(Dau=Aoa)GnRH-III(Dau=Aoa-GFLG)treatment100%55.7%42.4%Tumor weight (g)2.52.01.51.00.5100%59%50%0.00.012 14 16 18 20 22 24 26 28 30 32 34ControlGnRH-III(Dau=Aoa)GnRH-III(Dau=Aoa-GFLG)Days after tumor transplantationFig. 2. In vivo antitumor effect of GnRH-III – daunorubicin bioconjugates discussion.Our results indicate that oxime bond-linked daunorubicin-GnRH analog bioconjugatesrepresent a promising drug delivery system with potential applications in targeted cancerchemotherapy.AcknowledgmentsThis work was supported by grants from the Hungarian National Science Fund (OTKA NK 77485), theMinistry of Health (GVOP-3.2.1.-2004-04-0005/3) and the University of Konstanz (Zukunftskollegand AFF).References1. Singh, Y., Palombo, M., Sinko, P.J. Curr. Med. Chem. 15, 1802-1826 (2008).2. Mező, G., Manea, M. Exp. Opin. Drug Deliv. 7, 79-96 (2010).3. Mező, I., et al. Biochemical Peptides, Proteins & Nucleic Acids 2, 33-40 (1996).4. Sower, S.A., Chiang, Y.-C., Lovas, S., Conlon, J.M. Endocrinol. 132, 1125-31 (1993).5. Szabó, I., Manea, M., Orbán, et al. Bioconjugate Chem. 20, 656-665 (2009).533
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Miniprotein Engineering of the Knottin-like Scaffold Min-23-Solid-phase Synthesis and Oxidative Folding StrategiesFrederic Zoller 1 , Christain Hauer 2 , Annette Markert 1,2 ,Uwe Haberkorn 1,2 , and Walter Mier 21 Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, 69120,Heidelberg, Germany; 2Clinic for Nuclear Medicine, University Hospital Heidelberg,D-69120, Heidelberg, GermanyIntroductionMiniprotein scaffolds are currently emerging as novel recognition molecules and for thegeneration of epitope binding motifs for medical applications [1]. Owing to theirextraordinary stable architecture that tolerates multiple amino acid substitutions orinsertions, disufide-rich miniproteins are ideal scaffolds for combinatorial engineering [2].The knottin-like peptide scaffold Min-23 is rationally designed from the plant-occurringcyclotide ecballium elaterium trypsin inhibitor II (EETI-II) (Figure 1). This 23-mer peptideincorporating a cystine-stabilised beta-sheet (CSB) motif frames an autonomous foldingunit. The plasticity of the CSB motif allows the integration of a randomized affinityfunction into the stably folded framework [3]. These characteristics classify Min-23 as apeptide scaffold for lead generation using in vitro screening techniques, such as phage orribosome display [4]. However, engineering of cystine-knotted miniproteins is achallenging process, which requires an efficient solid-phase synthesis and oxidative foldingstrategies.EETI-II H 2 N-GCPRILMRCKQDSDCLAGCVCGPNGFCG-CONH 2cysteine protecting group (Fmoc-Cys(Trt)-OH or Fmoc-Cys(Acm)-OH)MIN-23 H 2 N-LXRCKQDSDCLAGSVCGPNGFCG-CONH 2norleucinesubstitutionpseudo-prolinedipeptidevariableloopFig. 1. Primary structure of EETI-II and Min-23. Key role amino acids for an optimizedFmoc/tBu-solid phase synthesis are highlighted.OtBuOCO NHHOOCOOCHNOHSOFig. 2. Structure of Fmoc-Asp(OtBu)-Cys(ψ H,DMP pro)-OH. This pseudoproline buildingblock avoids secondary structure formation. Moreover, it was shown to preventaspartimide formation and it acts as orthogonal protecting group for cysteine.Results and DiscussionThe initial solid-phase peptide synthesis of Min-23 revealed a high aggregation during thechain elongation within the helical section. This drawback was overcome usingcommercially available Asp-Ser-pseudoproline. In addition, the tertiary amide backbone ofthe Asp-Cys-pseudoproline building block was shown to prevent aspartimide formation(Figure 2) [5]. This optimization results in a crude peptide purity of 76% compared to only42% using standard SPPS-building blocks. For the subsequent oxidative peptide folding viadisulfide formation two different strategies were developed. The simultaneous formation oftwo disulfide bridges was achieved by air oxidation in a DMSO-free, buffered solution in534
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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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Proceedings of the 31 st European P
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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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