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Table 1. HDAC inhibitory activity and p21 promoter assay dataIC 50 (µM)CompoundHDAC1 HDAC4 HDAC6p21 promoterassay EC 1000(µM)Chlamydocin 0.00015 - 1.100 -a CHAP15 0.00044 - 0.038 -1 >100 >100 >100 >2502 65 52 >100 863 2.1 0.15 21 3.64 15 19 >100 >255 13 18 >100 >256 0.65 0.77 14 6.67 0.31 0.20 >100 0.47a CHAP, cyclic hydroxamic-acid-containing peptide; IC 50 half maximal inhibitoryconcentration; EC 1000 , Effective concentration (10 fold)designing, we focused on the proposed deacetylation mechanism. We selected chlamydocinscaffold as the carrier of functional group and synthesized seven cyclic tetrapeptides inwhich the epoxyketone moiety of chlamydocin was replaced by seven different functionalgroups or zinc ligands. The functional groups or zinc ligands are azide, triazole, borate,acrylamide, chloroacetamide, oxyacetic hydroxamate and dioxyacetone. The optimal ligandfrom these compounds can be utilized as the preferred ligand for other HDAC inhibitors.To compare the effectiveness of azide, triazole and borate versus epoxyketone, compoundsin which these groups and the epoxyketone are in the same position were synthesized(Figure 1, compounds 1-3). We next synthesized compounds 4-7 in which the carbonylgroups of the functional groups were in the same position as in chlamydocin. All thecompounds were characterized by high resolution FAB-MS. The synthesized compoundswere subjected to HDAC inhibitory activity using HDAC1, HDAC4, HDAC6 and p21promoter assay, the results of which are shown in Table 1. All the compounds were lesspotent than chlamydocin which reveals that the extent of zinc binding affinities for theseligands in mechanism of HDAC inhibition is less than that of chlamydocin.In conclusion, our aim was to find potent zinc ligands/functional groups, which mayhave enhanced binding affinities for zinc in HDAC inhibition mechanism. We haveintroduced new and known functional groups to the chlamydocin scaffold and evaluatedthese functional groups in the same molecular condition as HDAC inhibitory activity andcompared with the reported compounds, CHAP15 and chlamydocin [3].References1. Finnin, M.S., Donigian, J.R., Cohen, A., Richon, V.M., Rifkind, R.A., Marks, P.A., Breslow, R.,Pavletich, N.P. Nature 401, 188-193 (1999).2. De Schepper, S., Bruwiere, H., Verhulst, T., Steller, U., Andries, L., Wouters, W., Janicot, M., Arts,J., Van Heusden, J. J. Pharmacol. Exp. Ther. 304, 881-888 (2003).3. Furumai, R., Komatsu, Y., Nishino, N., Khochbin, S., Yoshida, M., Horinouchi, S. Proc. Natl.Acad.Sci. U.S.A. 98, 87-92 (2001).351
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Anti-Plasmodium Effects of Angiotensin II AnaloguesVani X. Oliveira Jr. 1 , Mayra Chamlian 1 , Ceres Maciel 2 ,Margareth L. Capurro 2 , and Antonio Miranda 31 Universidade Federal do ABC, Santo André, 09210-170, Brazil; 2 Universidade de SãoPaulo, São Paulo, 05508-000, Brazil; 3 Universidade Federal de São Paulo,São Paulo, 04023-900, BrazilIntroductionMalaria is a major parasitic disease affecting around 300-500 million people in the world.The efforts to control this disease are hampered by drug resistance in parasites, insecticideresistance in mosquitoes, and the lack of an effective vaccine. Recently, we performed astudy, which showed that Angiotensin II (AII) and some analogues are highly activeagainst immature and mature sporozoites of Plasmodium gallinaceum [1]. In an attempt toincrease the biological activity, we have scanned the whole AII sequence with i-(i+2) andi-(i+3) lactam bridge, consisting of the Asp-(X) n -Lys scaffold. The biological resultsindicated cell damage, after 60 minutes incubation with cyclic analogues VC-5, VC-17 andVC-19, which present the introduction of the side-chain to side-chain bridging element inthe N-terminal portion, and with the linear peptides VC-12, VC-26 and VC-28, that presentthe insertion of Asp and Lys residues in the C-terminal portion. These results suggest thatthe lactam bridge position in the sequence is important for the association of the moleculewith the sporozoite membrane; and that biological effect could be increased with theaddition of charged amino acid residues. This kind of approach may offer the basis fordevelopment the new drugs for malaria prevention and chemotherapy.Results and DiscussionThe peptides were synthesized by solid-phase methodology, using t-Boc strategy on achloromethylated resin [2]. Solid phase side-chain to side-chain cyclization of the peptideson the resin was performed by BOP/DIEA [3]. Peptides were cleaved from the resin usinganhydrous HF, purified by RP-HPLC and characterized by RP-HPLC, capillary zoneelectrophoresis, amino acid analysis and mass spectrometry [4].In the bioassays, the sporozoites were incubated with 40 µM digitonin, 60 µM AIIanalogues or PBS, for 60 minutes at 37°C. Cell membrane integrity was then monitored byfluorescence microscopy, adding 1 µl of propidium iodide. The biological results arepresented in the Figure 1.VC-30VC-29Fig. 1. Effects on membrane permeability of mature sporozoites when incubatedVC-28VC-27with AII and VC peptides.PeptidesVC-26VC-25VC-24VC-23VC-22VC-21VC-20VC-19VC-18VC-17VC-16VC-15VC-14VC-13VC-12VC-11VC-10VC-9VC-8VC-7VC-6VC-5VC-4VC-3VC-2VC-1Ang II0 10 20 30 40 50 60 70 80 90 100% Sporozoites FluorescentFig. 1. Effects on membrane permeability of mature sporozoites when incubated with AII andVC peptides.352
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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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