Synthesis, structure investigation and biological role of peptides, proteins and peptide nucleic acids  Page description

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Details of project

  
Identifier
49817
Type NI
Principal investigator Penke, Botond
Title in Hungarian Peptidek és fehérjék, és peptid-nukleinsavak szintézise, szerkezetvizsgálata és biológiai szerepe
Title in English Synthesis, structure investigation and biological role of peptides, proteins and peptide nucleic acids
Panel Natural Sciences large proposals
Department or equivalent Department of Medical Chemistry (University of Szeged)
Participants Bogár, Ferenc
Datki, Zsolt László
Ferenc, Györgyi
Fülöp, Lívia
Hornyák, Miklós Gábor
Huszár, Emoke
Janáky, Tamás
Kele, Zoltán
Leitgeb, Balázs
Letoha, Tamás Gyula
Molnár, Zsolt
Monostori, Éva
Pádár, Petra
Paragi, Gábor
Penke, Zsuzsa
Somlai, Csaba
Szájli, Emília
Szegedi, Viktor
Szemenyei, Erzsébet
Szűcs, Mária
Tóth, Gábor
Tóth, Géza
Tóth, Gézáné
Váradi, Györgyi
Yann, Verdier
Zarándi, Márta
Starting date 2005-01-01
Closing date 2007-12-31
Funding (in million HUF) 72.000
FTE (full time equivalent) 22.80
state closed project





 

Final report

  
Results in Hungarian
A neurodegeneratív betegségek kialakulásának jórészt közös mechanizmusa van: egy polipeptid vagy fehérje átalakul oldhatatlan aggregátummá, ez kicsapódik az idegsejtek között vagy a sejt belsejében és megakadályozza az ingerületvezetést, majd elpusztítja az idegsejteket. Alzheimer-kór modellkísérletekben igazoltuk, hogy a toxikus polipeptid (beta-amiloid 1-42) két fő aggregációs formája (Abeta-oligomer, ill. fibrillum) más receptorokon fejti ki hatását. A toxikus aggregátumok kialakulásában fontos szerepet játszhatnak a nehézfémionok, pl. a Zn2+, így a cink-kelátorok (pl. ACE-inhibitorok) az Alzheimer-kór potenciális gyógyszerei. Egy másik vegyületcsoport (peptidmimetikumok) úgy védi meg az idegsejteket, hogy beborítja az Abeta-aggregátumok felszínét és megakadályozza a kölcsönhatást a membránfehérjékkel (szabadalmi bejelentés). Gyógyszerek sejtbe jutását megkönnyítő, a sejtmembránon áthaladó peptid vektorokat terveztünk (penetratin származékok) és igazoltuk hatásmechanizmusukat (szabadalmi bejelentés). Egy humán beta-galaktozid kötő lektint (galektin-1) vizsgálva megállapítottuk, hogy igen hatásosan gátolja a gyulladásos és autoimmun folyamatokat, ez új immunoszupresszív stratégiát jelent. Az allergiás betegségek molekuláris hátterét vizsgálva a C3a szerkezetéből kiindulva olyan konformációsan gátolt peptidmimetikumokat állítottunk elő, amelyek megakadályozhatják a patológiás folyamatokat. Új szintézis módszereket dolgoztunk ki peptid nukleinsavak előállítására.
Results in English
Most of the neurodegenerative diseases possess a common mechanism: a polypeptide or protein forms by misfolding water insoluble aggregates that precipitate extra- or intracellularly. These toxic aggregates hinder interneuronal connections and destroy neurons. Our laboratory proved in model experiments of Alzheimer’s disease (AD) that the two main forms (oligomeric and fibrillar) of the toxic polypeptide beta-amyloid 1-42 affect different membrane receptors. Heavy metal ions, eng. Zn2+, may play key role in formation of toxic aggregates, therefore Zn-chelator drugs (e.g. ACE-inhibitors) could be used for the prevention of AD. Another group of compounds (peptides and peptidomimetics) protects neurons by covering the surface of Abeta-aggregates so preventing the interaction with membrane receptors (patent application). Novel peptide vector molecules (penetratin derivatives) were synthesized and studied, their mechanism of action was proven (patent application). Studying a human beta-galactoside binding lectin (galectin 1) it was proven, that the compound very effectively prevent inflammation and autoimmun processes providing a new strategy for immunosupression. The molecular background of allergic diseases was studied. Starting from the structure of the complement protein C3a, conformationally restricted peptidomimetics were synthesized that may prevent the pathological processes. Novel synthetic methods were introduced for the preparation of peptide nucleic acids.
Full text http://real.mtak.hu/2030/
Decision
Yes





 

List of publications

  
Letoha T., Somlai C., Takács T., Szabolcs A., Jármay K., Rakonczay Z. Jr., Hegyi P., Varga I., Kaszaki J., Krizbai I., Boros I., Duda E., Kusz E., Penke B.: A nuclear import inhibitory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis., World J. Gastroenterol 11, 990-999, 2005
Lain E., Penke B., Delacourte A., Gündisch D., Schröder H and Witter B: Effects of Aβ1-42 fibrils and of the tetrapeptide Pr-IIGL on the α7n AChR., Eur. J. of Neuroscience 21, 879-888, 2005
Letoha T., Gaál Sz., Somlai Cs., Venkei Zs., Glavinas H., Kusz E., Duda E., Czajlik A., Peták F. and Penke B.: Investigation of penetratin peptides. Part 2. In vitro uptake of penetratin and two of its derivatives., J. Peptide Sci, 11, 805-811, 2005
Hartai Z., Klivényi P., Janaky T., Penke B., Dux L., Vécsei L: Kynurenine metabolism in plasma and in red blood cells in Parkinson's disease., J Neurol Sci. 239, 31-35, 2005
Zana M., Juhász A., Rimanóczy A., Bjelik A., Baltás E., Ocsovszki I., Boda K., Penke B., Dobozy A., Kemény L., Janka Z., Kálmán J.: Alzheimer's lymphocytes are resistant to ultraviolet B-induced apoptosis., Neurobiol Aging. 27: 831-834, 2006
G.Tóth, E. Szemenyei, A. Keresztes, F. Fülöp: Tritium labelling of novel endomorphin analogues containing unnatural alfa and beta amino acids., Proceedings of 5th International Conference on Isotopes, Brussels, 2005
Szegedi V., Juhász G., Budai D., Penke B.: Divergent effects of Aß 1-42 on ionotropic glutamate receptor-mediated responses in CA1 neurons in vivo., Brain Research, 1062, 120-126, 2005
Kellermayer M.S.Z., Karsai Á., Kengyel A., Nagy A., Mártonfalvi Z., Grama L., Penke B.: Effect of lysine-28 side-chain acetylation on the nanomechanical behavior of Alzheimer amyloid ß 25-35 fibrils., J. Chem. Info. Model, 45, 1641-1646, 2005
Vas V, Fajka Boja R, Ion G, Dudics V, Monostori E, Uher F.: Biphasic effect of recombinant galectin-1 on the growth and death of early hematopoietic cells., STEM CELLS, 23, 279-287, 2005
Attila Keresztes, Annamária Páhi, Mária Szűcs, Ferenc Fülöp, Géza Tóth: New endomorphin-2 derivatives containing tritium labelled 2-aminocyclopentane carboxylic acid and 2-aminocyclohexane carboxylic acid., Scientica Pharmaceutica Supplement 1. 73, S212 (2005) Joint meeting on Medicinal Chemistry Vienna, June 20-23., 2005
G. Ferenc, Z. Kupihár, Z. Kele and L. Kovács: A convenient method for the synthesis of oligonucleotide-cationic peptide conjugates., Nucleosides Nucleotides Nucleic Acids 24, 1059-1061., 2005
G. Ferenc, P. Forgó, Z. Kele and L. Kovács: A regioselective synthesis of alkyl 2-(guanin-9-yl)acetates as PNA building blocks from 7-(4-nitrobenzyl)guanine derivatives., Collect. Czech. Chem. Commun. 70, 85-102., 2005
G. Ferenc, Z. Kele and L. Kovács: Determination of N9/N7 isomer ratio of alkyl (guaninyl)acetates by electrospray ionization tandem mass spectrometry., Rapid Commun. Mass Spectrom. 19, 236-240., 2005
P. Pádár, P. Forgó, Z. Kele, N. M. Howarth and L. Kovács: An intramolecular 1,3-dipolar cycloaddition reaction towards the synthesis of chiral azetidine nucleoside analogues: the D-gluco case., Nucleosides Nucleotides Nucleic Acids 24, 743-745., 2005
P. Pádár, M. Hornyák, P. Forgó, Z. Kele, G. Paragi, N. M. Howarth and L. Kovács: Intramolecular 1,3-dipolar cycloaddition of unsaturated nitrones derived from methyl alpha-D-glucopyranoside., Tetrahedron 61, 6816-6823., 2005
E. Szájli, G. Paragi and L. Kovács: A study of H-bonding of 3- and 5-substituted 6-aminouracils in duplex and triplex structures., Nucleosides Nucleotides Nucleic Acids 24, 907-910., 2005
Oksman M, Livonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lutjohann D, Hartmann T, Tanila H: Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice., Neurobiol Dis. 23: 563-572, 2006
Shemer I, Holmgren C, Min ilberter M, Sousa K M, Farkas T, Hartig W, Penke B, Burnashev N, Tanila H, Zilberter Y, Harkány T: Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptor, Eur J Neurosci 23: 2035-2047, 2006
Masman MF, Rodriguez AM, Svetaz L, Zacchino SA, Somlai C, Csizmadia IG, Penke B, Enriz RD: Synthesis and conformational analysis of His-Phe-Arg-Trp-NH(2) and analogues with antifungal properties., Bioorgan Med Chem 14: (22) 7604-7614, 2006
Law J M S, Szori M, Izsak R, Penke B, Csizmadia I G, Viskolcz B: Folded and unfolded conformations of the omega-3 polyunsaturated fatty acid family: CH3CH2(CH=CHCH2)(B)(CH2)(M)(COOH. First principles study, J. Phys Chem A 110: 6100-6111, 2006
Karsai A, Martonfalvi Zs, Nagy A, Grama L, Penke B, Kellermayer M S Z: Mechanical manipulation of Alzheimer's amyloid beta 1-42 fibrils, J. Struct Biol 155: (2) 316-326, 2006
Kalman E, Juhász A, Bogats G, Babik B, Rimanoczy A, Janka Z, Penke B, Palotás A: Elevated levels of inflammatory biomarkers in the cerebrospinal fluid after coronary artery bypass surgery are predictors of cognitive decline, Neurochem Int 48: 177-180, 2006
G Ion, R Fajka-Boja, F Kovacs, G Szebeni, I Gombos, A Czibula, J Matkó, E Monostori: Acid sphingomyelinase mediated release of ceramid is essential to trigger the mitochondrial pathway of apoptosis by galectin-1., Cell Signal 18, 1887-96, 2006
Kiss J, Kunstár A, Fajka-Boja R, Dudics V, Tóvári J, Légrádi Á, Monostori É, Uher F: A novel anti-inflammatory function of human galectin-1: inhibition of hematopoietic progenitor cell mobilization, Exp. Hemato, in press, 2006
Keresztes A, Tóth G, Fülöp F, Szűcs M,: Synthesis, radiolabeling and receptor binding of [3H] [(1S, 2R) ACPC2]endomorphin-2., Peptides, 27: 3315-3321, 2006
Tóth G, Keresztes A, Szemenyei E, Rónai A Z, Kóta E, Szűcs M, Fülöp F: Design, synthesis and radiolabeling of novel endomorphin analogues containig unnatural alfa-and beta-amino acids., Febs J. 273 (Suppl 1.): OP-97, p .69, 2006
Birkás E, Tóth G, Kertész I, Bakota L, Gulya K, Szűcs M: Receptorial characterization of a new delta opioid peptide antagonist, Tyr-Tic-(2S,3R)betaMePhe-Phe-OH., Febs J. 272 (Suppl.1.): C3-017P, p. 218, 2005
Keresztes A, Páhi A, Szűcs M, Fülöp F, Tóth G: New endomorphin-2 derivatives containing tritium labelled 2-aminocyclopentane carboxylic acid and 2-aminocyclohexane carboxylic acid., Scientica Pharmaceutica Supplement 1. 73, S212 Joint meeting on Medicinal Chemistry Vienna, June, 2005
Birkás E, Tóth G, Wen T, Pintar J, Szűcs M: A Tyr-Tic-(2S, 3R)betaMePhe-Phe-OH új delta opioid peptidantagonista in vivo és in vitro jellemzése egéragyi membránokban., Biokémia, XXX (3.), P-08, p. 66, 2006
Mahurter L, Garceau C, Marino J, Schmidhammer H, Tóth G, Gavril W. Pasternak: Separation of Binding affinity and intrinsic activity of the potent μ-opioid 14-methoximetopon., J. Pharm. Exp. Ther. 319, 247-253, 2006
P. Merino, P. Petra, I. Delso, M. Thirumalaikumar, T. Tejero, L. Kovács: Stereoselective synthesis of pyrrolidinyl glycines from nitrones: complementarity of nucleophilic addition and 1,3-dipolar cycloaddition., Tetrahedron Lett. 47, 5013-5016., 2006
P. Pádár, A. Bokros, P. Forgó, Z. Kele, N.M. Howarth, L. Kovács: Single diastereomers of polyhydroxylated 9-oxa-1-azabicyclo(4.2.1)nonanes from intramolecular 1,3-dipolar cycloaddition of omega-unsaturated nitrones., J. Org. Chem. 71, 8669-8672., 2006
Szabolcs A, Varga IS, Varga C, Berko A, Kaszaki J, Letoha T, Tiszlavics L, Sari R, Lonovics J, Takács T.: Beneficial effect of resveratrol on cholecystokinin-induced experimental pancreatitis., Eur J Pharmacol. 2006., 532: 187-93., 2006
Szabolcs A, Reiter RJ, Letoha T, Hegyi P, Papai G, Varga I, Jarmay K, Kaszaki J, Sari R, Rakonczay Z Jr, Lonovics J, Takács T: Effect of melatonin on the severity of L-arginine-induced experimental acute pancreatitis in rats., World J Gastroenterol, 12, 251-8., 2006
Fajka-Boja Roberta,Szebeni Gábor János, Tóth Gábor, Monostori Éva: A galektin-1 nem konvencionális endocitózisa., VII. Magyar Genetikai Kongresszus/ XIV. Sejt- és Fejlődésbiológiai Napok, Balatonfüred, 2007
G. Ferenc, P. Pádár, T. Janáky, Z. Szabó, G. K. Tóth, L. Kovács and Z. Kele: Capillary electrophoresis tandem mass spectrometry analysis of bromine-containing charged derivatives of peptides., J. Chromatogr. A 1159, 119-124., 2007
Z. Kupihár, Z. Timár, Z. Darula, D. J. Dellinger and M. H. Caruthers: An electrospray mass spectrometric method for accurate mass determination of highly acid-sensitive phosphoramidites, Rapid Commun. Mass Spectrom. 22, 533-540, 2008
Tóth, G. Ioja, E., Tömböly, Cs., Ballet, S., Tourwé, D., Péter, A., Martinek T., Chung, N., Schiller, W. P., Benyhe, S., Borsodi, A.: Beta-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe-peptides results in highly potent delta opioid antagonists, J. Med. Chem. 50., 328-333, 2007
E. Ioja, D. Tourwé, I. Kertész, G. Tóth, A. Borsodi, S. Benyhe: Novel diastereomeric opioid tetrapeptides exibit differing pharmacological activity profiles, Brain Research Bulletin 74, 119-129, 2007
E. Szemenyei, G. Tóth: Tritium labelling and degradation of 2'6' Dmt1-endomorphin-2, J. Labelled Comp. Radiopharm. 50, 1148-1152, 2007
E. Birkás, I. Kertész, G. Tóth, L. Bakota, K. Gulya, M. Szűcs: Synthesis and pharmacological characterization of a novel, highly potent, peptidomimetic delta-opioid radioantagonist, [H]Tyr-Tic-(2S,3R)-β-MePhe-Phe-OH., Neuropeptides 42, 57-67, 2008
G. Tóth, A. Keresztes, M.Szücs, E. Forró, F. Fülöp: Endomorphin analogs with alicyclic beta-amino acids, „5th Joint Meeting on Medicinal Chemistry”, Portoroz, Slovenia, (Ed. Danijel Kikelj). Medimond S.r.l. p. 47-50, 2007
Birkás E., Kertész I., Tóth G., Bakota L., Gulya K., Szűcs M: Egy új, konformációsan gátolt opioid peptid, a Tyr-Tic-(2S,3R)--MePhe-Phe-OH delta opioid antagonista jellegének kimutatása receptoriális és funkcionális vizsgálatokkal, MTA Peptidkémiai Munkabizottság Ülése, Balatonszemes, 2007
Birkás E., Tóth G., Wen T., Pintar J.P., Szűcs M: Tyr-Tic-(2S,3R)-b-MePhe-Phe-OH is a delta1 opioid receptor antagonist, XI. MITT Konferencia, Szeged, 2007
E. Birkás., G. Tóth, L. Bakota, K. Gulya, T. Wen, J.R. Pintar, M. Szűcs: Functional characterization of Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH., 36. INRC Congress, Berlin, Germany, 2007
A. Keresztes, M. Szűcs, F. Fülöp, G. Tóth: Endomorphin analogues with alicyclic β-amino acids: Influence on conformational characteristics on pharmacological profile., 19th Polish Peptide Symposium, Warsaw, Poland, 2007
Letoha T., Somlai C., Takács T., Szabolcs A., Jármay K., Rakonczay Z. Jr., Hegyi P., Varga I., Kaszaki J., Krizbai I., Boros I., Duda E., Kusz E., Penke B.: A nuclear import inhibitory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis., World J. Gastroenterol 11, 990-999, 2005
Karsai Á., Nagy A., Kengyel A., Mártonfalvi Z., Grama L., Penke B., Kellermayer M.S.Z.: Effect of lysine-28 side-chain acetylation on the nanomechanical behavior of Alzheimer amyloid ß 25-35 fibrils., J. Chem. Info. Model, 45, 1641-1646, 2005
Letoha T., Kusz E., Pápai G., Szabolcs A., Kaszaki J., Varga I., Takács T., Penke B., Duda E.: In vitro and in vivo NF kappaB inhibitory effects of the cell-penetrating penetratin peptide., Molecular Pharmacology, 69, 2027-2036, 2006
Verdier Y, Penke B.: Polypeptide and protein aggregates with neurotoxic properties in neurodegenerative disorders: Emphasis on beta-amyloid-induced dysfunction of receptor-mediated signal transduction. pathways., Current Signal Transduction Therapy, 1, 97-112, 2006
Zarándi M., Soós K., Fülöp L., Bozsó Zs, Datki Zs, Tóth G.K., Penke B.: Synthesis of Aβ(1-42) and its derivatives with improved efficiency, J.Peptide Sci., 13, 94-99, 2007
Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J,: Role of the toll-like receptor 4 in neuro-inflammation in Alzheimer's disease., Cellular Physiology and Biochemistry, 20, 947-956, 2007
Hetényi A., Fülöp L., Martinek A.T., Wéber E., Soós K., Penke B.: Ligand-induced flocculation of neurotoxic fibrillar Aβ(1-42) by noncovalent crosslinking., ChemBioChem, 9, 1-11, 2008
Datki Z.L., Hunya A., Penke B.: A novel and simple fluorescence method for the measurement of presynaptic vesicular zinc, Brain Research Bull, 74, 183-187, 2007
Karsai A., Grama L., Murvai U., Soos K., Penke B., Kellermayer M.S.Z.: Potassium-dependent oriented growth of amyloid beta 25-35 fibrils on mica., Nanotechnology, 18(34), 2007
Sipos E., Kurunczi A., Kasza A., Horvath J., Felszeghy K., Laroche S., Toldi J., Parducz A.,: Beta-amyloid pathology in the entorhinal cortex of rats induces memory deficits: Implications for, Neuroscience, 147, 28-36, 2007
Kellermayer M.S.Z., Karsai Á., Benke M., Soós K., Penke B.: Stepwise dynamics of epitaxially growing single amyloid fibrils., PNAS, 105, 141-144, 2008
Letoha T, Fehér LZ, Pecze L, Somlai C, Varga I, Kaszaki J, Tóth G, Vizler C, Tiszlavicz L, Takács T: Therapeutic proteasome inhibition in experimental acute pancreatitis., World J Gastroenterol.,13,4452-7., 2007
Zádori D., Datki Zs., Penke B: A krónikus agyi hipoperfúzió szerepe az Alzheimer-kór kialakulásában—tények és hipotézisek., Ideggyógyászati Szemle, 60, 428-437, 2007
Andrásfalvy M, Péterfy H, Tóth G K, Matkó J, Abramson J, Kerekes K, Vámosi Gy, Pecht I, Erdei A: The βSubunit of th Type I Fcε Receptor Is a Target for Peptides Inhibiting IgE-Mediated Secretory Response os Mast Cells., Journal of Immunology, 175: 2801-2806, 2005
Ion G, Fajka-Boja R , Toth GK, Caron M Monostori E.: Role of p56lck and ZAP70-mediated tyrosine phosphorylation in galectin-1-induced cell death., CELL DEATH DIFFER, 12(8):1145-7, 2005
Kellermayer M. S. Z., Grama L., Karsai Á. Nagy A., Kahn A., Datki Z. L. and Penke B: Reversible mechanical unzipping of amyloid Δ-fibrils., J. Biol. Chem.,280, 8464-8470., 2005
Letoha T., Somlai C., Takács T., Szabolcs A., Rakonczay Z., Jármay K., Szalontai T., Varga I., Kaszaki J., Boros I., Duda E., Hackler L., Kurucz I. And Penke B: The Proteasome Inhibitor MG132 Protects Against Acute Pancreatitis., Free Radical Biology and Medicine, 39, 1142-1151, 2005
Liu Y., Walter S., Stagi M., Cherny D., Letiembre M., Schulz-Schaiffer W., Heine H., Penke B., Neumann H., Fassbender K.: LP5 receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide., Brain 128, 1778-89, 2005
Márton Andrásfalvy, Hajna Péterfy, Gábor Tóth, János Matkó, Jakub Abramson, Krisztina Kerekes, György Vámosi, Israel Pecht, and Anna Erdei: The Subunit of the Type I Fc Receptor Is a Target for Peptides Inhibiting IgE-Mediated Secretory Response of Mast Cells, Journal of Immunology, 175 2801-2806, 2005
Szegedi V., Fülöp L., Farkas T., Rózsa E., Robotka H., Kis Z., Penke Z., Horváth S., Molnár Z., Datki Z., Soós K., Toldi J., Budai D., Zarándi M., Penke B.: Pentapeptides derived from Aβ1-42 protect neurons from the modulatory effect of Aβ fibrils – an in vitro and in vivo electrophysiological study., Neurobiology of Disease, 18, 499-508, 2005
Verdier Y., Huszár E., Penke B., Penke Zs., Woffendin G., Scigelova M., Fülöp L., Szűcs M., Medzihradszky K. Janáky T.: Identification of synaptic plasma membrane proteins co-precipitated with fibrillar beta-amyloid peptid., Journal of Neurochemistry, 94, 617-628, 2005
Hetényi C, Paragi G, Maran U, Timar Z, Karelson M, Penke B: Combination of a modified scoring function with two-dimensional descriptors for calculation of binding affinities of bulky, flexible ligands to proteins, J. Am Chem Soc 128: (4) 1233-1239 (2006), 2006
Szegedi V, Juhász G, Rozsa E, Juhász-Vedres G, Datki Z, Fülöp L, Bozso Z, Lakatos A, Laczko I, Farkas T, Kis Z, Tóth G, Soós K, Zarándi M, Budai D, Toldi J, Penke B: Endomorphin-2, an endogenous tetrapeptide, protects against Abeta1-42 in vitro and in vivo., Faseb Journal 20: 1191-3, 2006



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