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step, benzyl protection has been removed, Boc-protected tetrapeptide 5 has been activatedby N-hydroxysuccinimide in the presence of DCC with subsequent coupling with 4,9-dioxa-1,12-diaminododecane. After that, compound 6 was reacted with pentafluorophenylester of N-maleimidohexanoic acid. Deblocking of N -amino group led to bifunctionalcompound 7. The structures of the target compounds were confirmed by NMRspectroscopy and mass spectrometry.Amino groups of obtained compounds can allow connecting antisense oligonucleotideto N-terminal of peptides. Maleimide residue in such peptide-oligonucleotide conjugatespermits us to form covalent bond with albumin.BocAlaLeuAlaLeuOBzl1.OON2. TFA, CH 2 Cl 25FOFFF1. NaOH, EtOHO2. DCC ,HO N3. H 2 N OEDiPAF , EDiPAOH 2 NO NH 2BocAlaLeuAlaLeuAlaLeuAlaLeuONHOON HO6O7HNO NH 2Fig. 2. Synthetic scheme of bifunctional reagent based on the tetrapeptide.To verify substrate properties of obtained peptides, fluorescent derivatives 10 and 11 havebeen synthesized. To introduce fluorescein residue in AlaLeuAlaLeu or in compound 7N-hydroxysuccinimide ester of 5(6)-carboxyfluorescein has been used (Figure 3).OONOHO O OHOOOOH8OHO N , DCCOOOHNOOHNONHOHNOOHHO O OHAlaLeuAlaLeucompound 7EDiPAOEDiPAOOOOOAlaLeuAlaLeuHNNHOOOONHHOOOH10NOHOOOH11OFig. 3. Synthetic scheme of fluorescent derivatives of peptides.O9Obtained fluorescently labeled substrate can be used to trace the transport of therapeuticconstructs in the cells.AcknowledgmentsThe work was supported by integration project of SB RAS №88, Carl Zeiss-2010, №SC-3185.2010and grant of RFBR 09-04-01483-а.References1. Shiose, Y., Kuga, H., Ohki, H., Yamashita, F., Hashida, M. Bioconjugate Chem. 20, 60-70 (2009).2. Temming, K., Meyer, D., Zabinski, R., Dijkers, E., Poelstra, K., Molema, G., Kok, R. BioconjugateChem. 17, 1385-1394 (2006).3. Vasiljeva, O., Korovin, M., Gajda, M., Reinheckel, T., et al. Oncogene 27, 4191-4199 (2008).NO527
Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Amino Acids Esters of Acyclovir-Synthesis and AntiviralActivityIvanka Stankova 1 , Stoyan Shishkov 2 , Kalina Kostova 2 ,Daniel Todorov 2 , Luchia Mukova 3 , and Angel Galabov 31 Department of Chemistry, South-West University “Neofit Rilsky”, Blagoevgrad,Bulgaria; 2 Laboratory of Virology, Faculty of Biology, University of Sofia "St. Kl.Ohridski“, Sofia, Bulgaria; 3 The Stephan Angeloff Institute of Microbiology, BulgarianAcademy of Sciences, 1113, Sofia, BulgariaIntroductionFollowing the discovery of the first effective antiviral compound (idoxuridine) in 1959,nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirusinfections, have dominated antiviral therapy for several decades [1,2]. However, ACV andsimilar acyclic nucleosides suffer from low aqueous solubility and low bioavailabilityfollowing oral administration. Derivatives of acyclic nucleosides, typically esters, weredeveloped to overcome this problem and valacyclovir, the valine ester of ACV, was amongthe first of a new series of compounds that were readily metabolized upon oraladministration to produce the antiviral nucleoside in vivo, thus increasing the bioavaililityby several fold [3,4].One of the known approaches in the treatment of viral infection is the application of anumber of combinations of specific inhibitors with different mechanism of action, so thesimultaneous use of inhibtors with immunomodulators. This action leads to reducing thedose of the drug and its resistance. There are distinct effects of combinations of acyclovir(9-(2-hydroxyethoxymethyl)guanine) and cisplatin, rimantadine and ribavirin, oseltamivirand rimantadine. А significant synergy between ribavirin and oseltamivir against influenzavirus H9N2 in vivo is established [5-7].We expect that the obtained new analogues by coupling of acyclovir with 4-F-Phenylalnine (R,S) could possess a greater antiviral effect due to synergy. A two newanalogues of acyclovir and 4-F-Phenylalnine (R,S) were synthesized and screened for theiractivity in vitro against herpes simplex virus-1 (HSV-1) and influenza virus.Results and DiscussionSynthesis of acyclovir analoguesA mixture of 1 a-b and DDC in dimethylformamide (DMF) was stirred for 1h at 0°C undernitrogen atmosphere. A solution of acyclovir (Figure 1) and 4-N,N-(dimethylamino)-pyridine (DMAP) was added to the reaction mixture and stirred for 24h. Then DMF wasevaporated in vacuo and the residue was chromatographed on silica gel. The resulting whitesolid, Boc–(4-F)-Phe–ACV (R, S) was dissolved in 20 ml of TFA and stirred at 0°C for 1hto remove the Boc group. Following removal of the TFA in vacuum, 20 ml of ethyl acetatewas added to the oily reside. The solution was then added drop-wise to the cold diethylether. After filtration, 4-F-Phe–ACV (R,S) (TFA salt) was collected as white solid withhigh purity (>95%). Four milliliters of triethylamine (TEA) was added to 4-F-Phe–ACV(R,S) and kept for 15 min before dissolving it in 15 ml DMF. The 1 H and 13 C-NMR, massspectrawere consistent with desired structure (2 a-b).FBoc-AA1 a-biiiFCONH 2O2 a-bONNONNHNH 2(i) acyclovir / DCC/DMAP ; (ii) TFA/CH 2CH 2Protected AA: 1 a) Boc-(4-F)-Phenylalanine (R);1 b) Boc-(4-F)-Phenylalanine (S).Fig. 1. Synthesis of acyclovir analogues with 4-F-Phenylalanine (R,S).Figure 1. Synthesis of acyclovir analogues with 4-F-Phenylalanine (R, S)528
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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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