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Artykuły w czasopismach na temat "Γ Peptide"
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Möller, Carolina, i Frank Marí. "A vasopressin/oxytocin-related conopeptide with γ-carboxyglutamate at position 8". Biochemical Journal 404, nr 3 (29.05.2007): 413–19. http://dx.doi.org/10.1042/bj20061480.
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Vasopressins and oxytocins are homologous, ubiquitous and multifunctional peptides present in animals. Conopressins are vasopressin/oxytocin-related peptides that have been found in the venom of cone snails, a genus of marine predatory molluscs that envenom their prey with a complex mixture of neuroactive peptides. In the present paper, we report the purification and characterization of a unique conopressin isolated from the venom of Conus villepinii, a vermivorous cone snail species from the western Atlantic Ocean. This novel peptide, designated γ-conopressin-vil, has the sequence CLIQDCPγG* (γ is γ-carboxyglutamate and * is C-terminal amidation). The unique feature of this vasopressin/oxytocin-like peptide is that the eighth residue is γ-carboxyglutamate instead of a neutral or basic residue; therefore it could not be directly classified into either the vasopressin or the oxytocin peptide families. Nano-NMR spectroscopy of the peptide isolated directly from the cone snails revealed that the native γ-conopressin-vil undergoes structural changes in the presence of calcium. This suggests that the peptide binds calcium, and the calcium-binding process is mediated by the γ-carboxyglutamate residue. However, the negatively charged residues in the sequence of γ-conopressin-vil may mediate calcium binding by a novel mechanism not observed in other peptides of this family.
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Mason, R. D., M. I. Bowmer, C. M. Howley i M. D. Grant. "Cross-Reactive Cytotoxic T Lymphocytes against Human Immunodeficiency Virus Type 1 Protease and Gamma Interferon-Inducible Protein 30". Journal of Virology 79, nr 9 (1.05.2005): 5529–36. http://dx.doi.org/10.1128/jvi.79.9.5529-5536.2005.
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ABSTRACT The gamma interferon (IFN-γ)-inducible protein 30 (IP-30) signal peptide −11 to −3 (LLDVPTAAV) is a prominent self peptide expressed with the class I human histocompatibility leukocyte antigen A2 (HLA-A2). Stimulation of peripheral blood mononuclear cells (PBMC) from HLA-A2 human immunodeficiency virus type 1 (HIV-1)-infected individuals with an HLA-A2-restricted HIV protease (PR) peptide 76-84 (LVGPTPVNI) activated cytotoxic T lymphocytes (CTL) against the IP-30 signal peptide. Since HIV-1 PR 76-84 stimulated CD8+ T cells from these individuals to secrete IFN-γ, we tested whether the activation of IP-30-specific CTL in vitro resulted from T-cell cross-reactivity or from up-regulation of IP-30 by IFN-γ. Neither high levels of exogenous IFN-γ nor incubation of PBMC with other HIV peptides triggering substantial IFN-γ release activated IP-30-specific CTL. Although the IP-30 signal peptide did not stimulate IFN-γ release from freshly isolated PBMC, it activated CTL in vitro against itself and HIV PR 76-84. Peptide-stimulated IFN-γ release, cold target inhibition, and HLA-A2/immunoglobulin dimer-mediated binding and depletion of effector cells all indicated that in vitro stimulation with HIV PR 76-84 or the IP-30 signal peptide activated a comparable population of cross-reactive effector cells. Neither IP-30 nor HIV PR 76-84 activated CTL against themselves following in vitro stimulation of PBMC from non-HIV-infected HLA-A2 individuals. Peptide titrations indicated higher-avidity T-cell interactions with HIV PR 76-84 than with the IP-30 signal peptide. These data indicate that HIV PR 76-84 is a heteroclitic variant of the IP-30 signal peptide −11 to −3, which has implications for immune memory and autoimmunity.
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Huang, Xiao-Li, Zheng Fan, LuAnn Borowski i Charles R. Rinaldo. "Multiple T-Cell Responses to Human Immunodeficiency Virus Type 1 Are Enhanced by Dendritic Cells". Clinical and Vaccine Immunology 16, nr 10 (19.08.2009): 1504–16. http://dx.doi.org/10.1128/cvi.00104-09.
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ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific T-cell reactivity has been related to protection from disease progression. Optimal T-cell reactivity to HIV-1 presumably requires antigen processing and presentation by professional antigen-presenting cells, particularly dendritic cells (DC). Here we examined whether multiple HIV-1-specific T-cell functions are enhanced by stimulation with HIV-1 peptide-loaded DC derived from HIV-1-infected subjects on antiretroviral therapy. We first found that mature DC increased the number of gamma interferon (IFN-γ)-producing T cells detected by enzyme-linked immunospot assay to overlapping 15-mer peptides of HIV-1 Gag and Nef, compared to stimulation with peptide-loaded, immature DC or to peptides without DC. IFN-γ production was lower in response to large pools of the Gag and Nef peptides, regardless of presentation by DC. We further observed that HIV-1 peptide-loaded, mature DC stimulated greater CD8+ and CD4+ T-cell proliferation than did the peptides without DC and that T-cell proliferation was lower in response to larger pools of the peptides. The lower T-cell IFN-γ and proliferation responses to the larger peptide pools were related to lower T-cell viability. Finally, the number of polyfunctional CD8+ and CD4+ T cells stimulated by HIV-1 peptide-loaded, mature DC, defined as positive by intracellular staining for more than one immune mediator (IFN-γ, interleukin 2, tumor necrosis factor alpha, macrophage inhibitory protein 1β, or CD107a), was greater than that stimulated by the peptides alone. These results indicate that DC can enhance multiple types of HIV-1-specific T-cell functions.
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Flood, Veronica H., Hamid A. Al-Mondhiry, Antony C. Bakke i David H. Farrell. "Fibrinogen Hershey IV: A Novel Dysfibrinogen with a γ V411I Mutation in the Integrin αIibβ3 Binding Site." Blood 106, nr 11 (16.11.2005): 2133. http://dx.doi.org/10.1182/blood.v106.11.2133.2133.
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Abstract The C-terminal segment of the fibrinogen γ chain plays a crucial role in platelet aggregation via its interaction with the platelet receptor αIIbβ3. It is well established that the last four amino acids of the γ chain (408 to 411) are critical for this function, as mutations or deletions of this region abrogate fibrinogen’s ability to bind αIIbβ3. We describe here the first naturally occurring fibrinogen mutation affecting the C-terminal region of the γ chain and investigate its effects on platelet interactions. The proband, a 49-year-old woman, was diagnosed with dysfibrinogenemia based on a prolonged thrombin time and low fibrinogen activity (55 mg/dL). Her bleeding history was significant for menorrhagia and one episode of post-operative hemorrhage. DNA sequencing of the fibrinogen genes demonstrated heterozygosity for two mutations, γ R275C and γ V411I. The latter γ V411I mutation represents a novel mutation affecting the C-terminal amino acid of the γ chain. We hypothesized that this mutation would decrease fibrinogen’s affinity for the platelet receptor αIIbβ3. In order to isolate the effects of this mutation on fibrinogen-platelet binding, γ 400-411 dodecapeptides were synthesized to mimic the C-terminal γ chain sequence. One peptide contained the wild-type sequence ending in valine (γ 400-V411), and the second peptide incorporated the isoleucine mutation (γ 400-I411). Previous studies have demonstrated that the wild type γ 400-V411 dodecapeptide inhibits platelet aggregation by competing for fibrinogen binding to αIIbβ3. We performed platelet aggregation studies comparing inhibition of aggregation with the wild-type γ 400-V411 and the mutant γ 400-I411 peptides. Washed platelets were obtained from a normal donor, and platelet aggregation monitored using the agonist ADP. The IC50 for the initial rate of aggregation with the γ 400-I411 peptide was 214 μM, compared to 133 μM with the wild-type peptide. We then examined the extent of aggregation in the presence of either wild-type or mutant peptide. Consistent with the previous results, total aggregation was lower with the wild-type peptide compared to the mutant peptide. The IC50 for the γ 400-I411 peptide was 450 μM compared to 250 μM with the γ 400-V411 peptide. Overall, these findings suggest that the γ I411 mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available amount of wild-type fibrinogen may be sufficient to support platelet aggregation. The bleeding diathesis observed for the proband could therefore reflect other factors, especially the γ R275C mutation.
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Farrell, David H., Rehana S. Lovely i Lynn K. Boshkov. "Inhibition of Thrombin Cleavage of Factor VIII by Fibrinogen γ’ Chain Carboxyl Terminus." Blood 106, nr 11 (16.11.2005): 1957. http://dx.doi.org/10.1182/blood.v106.11.1957.1957.
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Fibrinogen can contain two types of γ chains, γA and γ’, that have identical sequences for the first 407 amino acids, but differ at their carboxyl termini. The γA chain contains four amino acids from γA 408–411, whereas the γ’ chain contains a different, highly anionic sequence of twenty amino acids from γ’ 408–427. This small change results in profound differences in the fibrinogen isoforms containing these distinct chains. The γ’ chain contains high affinity binding sites for zymogen factor XIII and for thrombin, and fibrinogen containing γ’ chains forms fibrin clots that are resistant to fibrinolysis. We have shown previously that the fibrinogen γ’ chain carboxyl terminus binds to thrombin exosite II, an anion-binding exosite known for its heparin binding activity. Recent reports show that the presence of the γ’ chain in fibrinogen reduces prothrombin activation in whole plasma assays. This inhibition may correspond to an activity originally described by Seegers in 1945 as “antithrombin I”, the adsorption of thrombin to fibrin. We have therefore investigated the enzymatic effects of γ’ peptide binding to thrombin in order to determine the role of the γ’ chain in the inhibition of prothrombin activation. In whole plasma, the γ’410–427 peptide prolonged the activated partial thromboplastin time (aPTT) in a dose-dependent manner, causing a delay in clotting from 29 seconds to 47 seconds at a concentration of 500 μM. A scrambled control peptide at the same concentration had little effect, increasing the clotting time to only 31.4 seconds. A series of γ’ deletion peptides were tested for their ability to prolong the aPTT. The inhibitory effect of the peptides corresponded in rank order to their thrombin binding affinity. In contrast to the aPTT, the prothrombin time increased only slightly from 11.7 seconds to 12.8 seconds (INR from 1.04 to 1.14) with the γ’410–427 peptide. This suggested that the γ’ peptide exerted its inhibitory effect on (a) component(s) of the intrinsic pathway, rather than the extrinsic pathway. We therefore investigated the effect of the γ’ peptide on thrombin activation of factor VIII, a thrombin substrate that, unlike factor V, is unique to the intrinsic pathway. Using purified factor VIII and thrombin in vitro, we showed that the γ’ peptide inhibited thrombin cleavage of factor VIII. However, this inhibitory effect was not due to direct inhibition of the thrombin active site, since the free γ’ peptide had little effect on thrombin cleavage of a small peptidyl substrate, tosyl-glycyl-prolyl-arginine-4-nitranilide acetate. These results suggest that factor VIII interactions with thrombin exosite II are essential for efficient cleavage of factor VIII, and support recent findings by others that interactions between thrombin exosite II and the A2 domain of factor VIII facilitate thrombin-catalyzed cleavage. These findings may explain, at least in part, the inhibitory effect of the γ’ chain on prothrombin activation in plasma.
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Hirano, Naoto, Marcus O. Butler, Zhinan Xia, Seiji Kojima i Lee M. Nadler. "γ-Globin, a Tumor-Associated Antigen for Juvenile Myelomonocytic Leukemia (JMML): A Cell-Based Approach To Identify Tumor Antigenic Epitopes That Are Naturally Processed and Presented." Blood 104, nr 11 (16.11.2004): 3418. http://dx.doi.org/10.1182/blood.v104.11.3418.3418.
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Abstract Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder of early childhood. Although allogeneic stem cell transplantation can induce long-term remissions, relapse rates remain high, and innovative approaches are needed. Since donor lymphocyte infusion in JMML is efficacious, T cell mediated immunotherapy may be effective, and appropriate antigenic targets must be identified. One candidate tumor-associated antigen for the immunotherapy of JMML is γ-globin, which is expressed at high levels in most JMML patients. Most clonogenic JMML cells constitutively express this onco-fetal protein, which is not necessary for the normal erythropoesis of children and adults. To determine whether γ-globin can serve as a target for immunotherapy in JMML, we sought to determine whether γ-globin is naturally processed and presented by the HLA complex. Using conventional bioinformatic techniques and the T2 binding assay to predict candidate epitopes, we identified 4 γ-globin derived peptides (g031, g071, g105, and g106) that were predicted to bind to the HLA-A2 molecule in vitro. Since this strategy provides no evidence for which predicted epitopes are processed and presented by tumor cells in vivo, we employed a biochemical strategy to determine which peptides are naturally processed and presented. This step is critical in certifying that a candidate peptide epitope is an appropriate target for immunotherapy treatments. Using our K562-derived artificial APC (aAPC), an APC that expresses A2 and no other HLA allele, we introduced the EGFP-γ-globin fusion gene. We then acid stripped peptides directly from the surface of one billion aAPC/EGFP-γ-globin cells without subjecting the cells to detergent mediated lysis. Peptides less than 5 kDa in size were fractionated by reverse phased HPLC analysis and analyzed by mass spectrometry. We identified two mass spectrometry peaks which corresponded to γ-globin derived peptides, g031 and g105. Of these, the identity of one peak, g105, was successfully confirmed by peptide sequencing, providing strong evidence that g105 is naturally processed and presented by aAPC/EGFP-γ-globin cells. Next, to confirm that g105 is processed and presented by primary JMML cells, we generated γ-globin specific CD8+ cytotoxic T cells (CTL) from A2 positive healthy donors using synthetic g105 peptide. γ-Globin specific CTL were able to specifically cytolyze A2+ γ-globin+ JMML cells but not A2+ γ-globin- JMML cells. Specific cytotoxicity was blocked by anti-A2 mAb but not isotype control. These results show for the first time that the γ-globin derived peptide, g105, can serve as a target epitope for the CTL directed immunotherapy of JMML. Furthermore, these results illustrate an innovative aAPC based strategy that can identify the antigenic peptide epitopes of putative tumor associated antigens that are naturally processed by tumor cells, presented via HLA class I, and can serve as targets for effective anti-cancer immunotherapy.
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Hirao, Takashi, Masahide Sato, Akira Shirahata i Yoshiyuki Kamio. "Covalent Linkage of Polyamines to Peptidoglycan inAnaerovibrio lipolytica". Journal of Bacteriology 182, nr 4 (15.02.2000): 1154–57. http://dx.doi.org/10.1128/jb.182.4.1154-1157.2000.
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ABSTRACT Spermidine and cadaverine were found to be constituents of the cell wall peptidoglycan of Anaerovibrio lipolytica, a strictly anaerobic bacterium. The peptidoglycan was degraded with theN-acetylmuramyl-l-alanine amidase and endopeptidase into two peptide fragments, peptide I and peptide II, at a molar ratio of 4:1. Peptides I and II were identified asl-alanine–d-glutamic acid(αcadaverine)γ meso-diaminopimelic acid (DAP)–d-alanine andl-alanine–d-glutamic acid(αspermidine)γ meso-DAP–d-alanine, respectively. The N1-amino group of spermidine was linked to the α-carboxyl group of the d-glutamic acid residue of peptide II.
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Mujtaba, Mustafa. "Antiviral inducing properties of staphylococcal enterotoxin mimetic peptides (VAC9P.1065)". Journal of Immunology 194, nr 1_Supplement (1.05.2015): 145.5. http://dx.doi.org/10.4049/jimmunol.194.supp.145.5.
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Abstract Superantigens, like the staphylococcal enterotoxins, activate vast numbers of T-cells to produce large amounts of cytokines, including interferon-gamma (IFN-γ), and eventually cause these cells to undergo apoptosis. The objective of this research was to design mimetic peptides of staphylococcal enterotoxins that are not toxic to cells, but can produce antiviral activity in cells via production of IFN-γ. Based on the amino acid sequences of staphylococcal enterotoxins (SE) A, B, C, and toxic shock syndrome toxin, peptides were designed to mimic the antigenic sites of these superantigens. Whole protein superantigens (SEA) at concentrations ranging from 1.0 to 10.0ng/mL stimulated T-cell proliferation and induced IFN-γ production. Superantigen concentrations at or above 100ng/mL showed cellular toxicity. Of the eight mimetic peptides tested, SEA 3 was the only peptide that induced IFN-γ production, as determined by the IFN-γ ELISA kit, in HPBMC but did not induce cellular proliferation. SEA1, SEA2, and TSST peptides induced cellular proliferation but no IFN-γ stimulation. The peptides showed no toxicity directly on HeLa cells or HPBMC at 100 ug/mL or lower. Cell supernatant from the SEA3 peptide treated HPBMC also had antiviral activity against vesicular stomatitis virus. Thus, this study showed that mimetic peptides of superantigens could be developed that can induce T-cells to produce IFN-γ without the cellular toxicity associated with superantigens.
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Passero, Christopher J., Marcelo D. Carattino, Ossama B. Kashlan, Mike M. Myerburg, Rebecca P. Hughey i Thomas R. Kleyman. "Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel". American Journal of Physiology-Renal Physiology 299, nr 4 (październik 2010): F854—F861. http://dx.doi.org/10.1152/ajprenal.00316.2010.
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Proteases activate the epithelial sodium channel (ENaC) by cleaving the large extracellular domains of the α- and γ-subunits and releasing peptides with inhibitory properties. Furin and prostasin activate mouse ENaC by cleaving the γ-subunit at sites flanking a 43 residue inhibitory tract (γE144-K186). To determine whether there is a minimal inhibitory region within this 43 residue tract, we generated serial deletions in the inhibitory tract of the γ-subunit in channels resistant to cleavage by furin and prostasin. We found that partial or complete deletion of a short segment in the γ-subunit, R158-N171, enhanced channel activity. Synthetic peptides overlapping this segment in the γ-subunit further identified a key 11-mer tract, R158-F168 (RFLNLIPLLVF), which inhibited wild-type ENaC expressed in Xenopus laevis oocytes, and endogenous channels in mpkCCD cells and human airway epithelia. Further studies with amino acid-substituted peptides defined residues that are required for inhibition in this key 11-mer tract. The presence of the native γ inhibitory tract in ENaC weakened the intrinsic binding constant of the 11-mer peptide inhibitor, suggesting that the γ inhibitory tract and the 11-mer peptide interact at overlapping sites within the channel.
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Zeng, Yi, Michael W. Graner, Sylvia Thompson, Marilyn Marron i Emmanuel Katsanis. "Induction of BCR-ABL–specific immunity following vaccination with chaperone-rich cell lysates derived from BCR-ABL+ tumor cells". Blood 105, nr 5 (1.03.2005): 2016–22. http://dx.doi.org/10.1182/blood-2004-05-1915.
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AbstractWe have previously reported that chaperonerich cell lysates (CRCL) derived from the BCR-ABL+ 12B1 leukemia activate dendritic cells (DCs) and stimulate leukemia-specific immune responses. Because CRCL contain a variety of heat shock/chaperone proteins, we theorized that CRCL obtained from BCR-ABL+ leukemias are likely to chaperone BCR-ABL–derived fusion peptides and that DCs pulsed with 12B1 CRCL could cross-present BCR-ABL fusion peptides to T cells. We found that splenocytes from mice vaccinated with BCR-ABL+ leukemia-derived CRCL secreted interferon-γ (IFN-γ) when restimulated with a BCR-ABL peptide, GFKQSSKAL, indicating that BCR-ABL peptides are chaperoned by leukemia-derived CRCL. We next eluted peptides from 12B1 leukemia-derived CRCL and used high-pressure liquid chromatography (HPLC) fractions to restimulate splenocytes harvested from mice vaccinated with DC/GFKQSSKAL or DC/12B1 CRCL. We found that the same peptide fractions derived from 12B1 CRCL and from “refractionated” GFKQSSKAL stimulated IFN-γ production, suggesting the presence of BCR-ABL peptides in the peptide repertoire of 12B1 CRCL. We also demonstrated that immunization with DCs loaded with leukemia-derived CRCL induced BCR-ABL–specific cytotoxic T lymphocytes (CTLs) in vivo. Moreover, mice immunized with DCs pulsed with 12B1-derived CRCL had superior survival (60%) when compared with those immunized with DCs pulsed with BCR-ABL peptide (20%), indicating that CRCL vaccines provide additional immune stimulus over and above individual peptide vaccination.
Rozprawy doktorskie na temat "Γ Peptide"
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Rosés, Subirós Cristina. "Solid-phase synthesis of cell-penetrating γ-peptide/antimicrobial peptide conjugates and of cyclic lipodepsipeptides derived from fengycins". Doctoral thesis, Universitat de Girona, 2016. http://hdl.handle.net/10803/393895.
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This thesis is focused on the development of synthetic approaches to obtain new bioactive peptides. The first part deals with the design of new antimicrobial peptide/cell-penetrating peptide conjugates as anticancer agents. Their conjugation enhanced the activity of the antimicrobial peptides against cancer cells while maintained their low toxicity. These compounds are interesting for the design of new anticancer agents. On the second part, a new versatile methodology for the synthesis of natural fengycin derivatives is described. Our strategy represents the first synthetic approach for the total solid-phase synthesis of these cyclic lipodepsipeptides and can be easily adapted to obtain a wide range of analogues.Aquesta tesi doctoral s’ha centrat en el desenvolupament d’estratègies sintètiques útils per a l’obtenció de nous pèptids bioactius. Primerament, s’han dissenyat nous pèptids conjugats antitumorals a través de la unió d’un pèptid antimicrobià i un cell-pentrating peptide. Aquesta conjugació augmenta l’activitat antitumoral del pèptid mantenint la toxicitat baixa. Aquests conjugats són interessants pel desenvolupament de nous agents antitumorals. A continuació, s’ha desenvolupat una metodologia per a la preparació de pèptids cíclics derivats de les fengicines. Aquesta metodologia representa la primera estratègia sintètica descrita per a l’obtenció en fase sòlida d’aquesta família de ciclolipodepsipèptids i pot ser fàcilment adaptada per a l’obtenció d’una àmplia varietat d’anàlegs.
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Halie, Delphine. "Synthèse diastéréosélective de mimes du peptide RGD". Paris 5, 2006. http://www.theses.fr/2006PA05P639.
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Li, Yaqiong. "Gamma AApeptides as Host Defense Peptide Mimics". Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6301.
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There has been increasing concern regarding the emergence of multi-drug resistant pathogens. The resistance develops when pathogens, especially bacteria, are frequently exposed to conventional antibiotics, as they are heavily used in both human and livestock. This is due to the high target specificity of conventional antibiotics, which places pathogens in high selective pressures and eventually results in drug resistant by mutations. To address this issue, global actions and cooperation are needed. At the same time, new technologies and strategies need to be developed. Host defense peptides (HDPs) are widely found in the innate immune system. They show both direct antimicrobial properties and immunomodulatory activities. The multifaceted functions of HPDs make them less likely to promote antimicrobial resistance. Thus, they are promising as new therapeutics to treat multi-drug resistant infections. In fact, several drug candidates derived from HDPs have entered the clinical trial, but none of them got into the clinic. This is due to several challenges associated with HDPs, such as low in vivo stability, high cost of manufacturing, and toxicity to mammalian cells. In this dissertation, we explored the ability of a new type of unnatural scaffolds (γ-AApeptides) to mimic the functions of HDPs, including both broad spectrum antimicrobial properties and immunomodulatory activities. Furthermore, the efforts to identify simpler and more drug like γ-AApeptide based antimicrobial agents were also discussed. The findings in this dissertation may lead to the development of potential drug candidates to treat multi-drug resistant infections.
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Shibata, Masayuki. "Studies on “kokumi” taste components in soybean seeds : Identification, content determination and efficient extraction". Kyoto University, 2018. http://hdl.handle.net/2433/233823.
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Pardossi-Piquard, Raphaëlle. "Le complexe γ-sécrétase : implications dans la régulation de l'apoptose et la dégradation du peptide amyloïde". Nice, 2005. http://www.theses.fr/2005NICE4053.
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L'activité g-secretase dépendante des présénilines est impliquée dans la production du peptide A-beta et nécessite la formation d'un complexe de haut poids moléculaire contenant au moins 4 protéines partenaires : la préséniline 1 ou 2, la nicastrine, Aph1 et Pen2. Au cours de ma thèse j'ai pu montré une implication de ce complexe gamma-sécrétase dépendant des présénilines dans la régulation de l'apoptose et la dégradation du peptide A-beta. L'implication des présénilines dans les processus de mort cellulaire a déjà été décrite dans la littérature, la présénilines 2 joue un rôle pro-apoptotique alors que la préséniline 1 semble protéger les cellules de l'apoptose. Nos expériences montrent pour la première fois, un phénotype anti-apoptotique de la nicastrine qui est associé à une baisse de l'expression et de l'activité transcriptionnelle de p53. Nous avons également mis en évidence une composante de cette réponse indépendante de p53 puisqu'en absence de p53, la nicastrine présente toujours un phénotype antiapoptotique. Par ailleurs, nous avons établi une fonction du complexe gamma-sécrétase dépendant des présénilines dans la régulation de la dégradation du peptide A-beta. En effet, l'activité gamma -secretase dépendante des présénilines libère en plus du peptide A-beta, sa contrepartie cytosolique, le fragment AICD qui est transloqué au noyau. Nous avons montré pour la première fois, que ce fragment AICD pouvait réguler la transcription de la néprilysine, un enzyme de dégradation du peptide A-beta.
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Wan, Yang. "Synthesis of β,γ-diamino acids and their use to design new analogues of the antimicrobial peptide Gramicidin Septide antimicrobien, la Gramicidine S". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS407/document.
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Dans notre groupe, nous nous intéressons au développement de peptides contenant des acides γ-aminés. Comme d’autres peptides contenant des acides aminés non naturels, ils ont montré leur capacité à posséder des conformations stables et/ou des propriétés biologiques intéressantes. De plus, ces peptides sont généralement résistant à la protéolyse. Dans l’objectif de synthétiser des acides -diaminés sous la forme d’un seul stéréoisomère, nous avons développé une voie de synthèse reposant sur une réaction de Blaise suivie d’une réduction diastéréosélective. En appliquant cette méthode, nous avons synthétisé des acides β,γ-diaminés dérivés de la D-phénylalanine et de l’acide L-glutamique. Le premier a été utilisé pour concevoir des analogues d’un peptide antimicrobien, la gramicidine S. Comparé à la molécule parent, les analogues ont montré une cytotoxicité beaucoup moins importante pour les cellules hôtes tout en conservant une activité antibactérienne intéressante. Cette étude nous a donné de meilleures connaissances pour développer d’autres analogues de la gramicidine S ainsi que d’autres peptides antimicrobiens. Nous avons également effectué de nombreuses optimisations pour synthétiser de façon efficace des acides β,γ-diaminés cycliques à partir de l’acide L-glutamique. Les oligomères incorporant ces acides β,γ-diaminés et des acides α-aminés ont montré un fort potentiel pour l’adoption de conformations stables. Ces études vont être poursuiviesIn our group, we are interested in developing peptides containing β,γ-diamino acids . Along with many other peptides containing unnatural amino acids, they have shown the ability to possess stable conformations and/or interesting biological activities. Moreover, those peptides are usually more resistant to proteolysis. In order to synthesize stereopure γ-amino acids, we have developed a synthetic route using Blaise reaction and subsequent diastereoselective reduction as key reactions. Through applying this method, we have synthesized β,γ-diamino acids derived from D-phenylalanine and L-glutamic acid. The former β,γ-diamino acid was used for designing antimicrobial peptide gramicidin S analogues. Compared with mother molecule, the analogues exerted much less host cell cytotoxicity while remaining interesting antibacterial activity. Meanwhile, it gave us more knowledge for further developing analogues of gramicidin S as well as other antimicrobial peptides. We also paid lots of effort to efficiently synthesize cyclic β,γ-diamino acids starting from L-glutamic acid. Interestingly, when oligomers incorporating this β,γ-diamino acids and α-amino acids, they have shown the potential to adopt stable conformations. The following studies will be continuously investigated
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Nimmagadda, Alekhya. "Design, Synthesis, Applications of Polymers and Dendrimers". Scholar Commons, 2017. https://scholarcommons.usf.edu/etd/7430.
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WHO has reported that antibiotic resistance is the third major cause of human death all over the globe. Recent study, has focused on the development of new antibacterial resistance drugs. Herein, we tried to synthesis a series of polymers that can mimic the HDPs. HDPs can target the bacterial cell membrane and they have less chances to develop bacterial resistance. We synthesized the amphiphilic polycarbonates that are highly selective to Gram-positive bacteria, including multidrug resistant pathogens. The membrane disruption activity of these polymers was proved by fluorescence and TEM studies and the drug resistance study showed that the polymers don’t develop bacterial resistance. In order to further design the molecules that can target a broad spectrum of bacteria, we have designed a series of lipidated dendrimers that can target the Gram-positive and Gram-negative bacteria. These dendrimers mimic the HDPs and target the bacterial cell membrane. Dendrimers are reported to inhibit the formation of bacterial biofilm which makes them promising for their future development of antibiotic agents.
Apart from the synthesis of polymers and dendrimers as antibacterial agents, we have designed a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold and small dimeric cyclic guanidine derivatives. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). Lastly, we also demonstrate that these molecules have excellent in vivo activity against MRSA in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.
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Awada, Hawraà. "Synthèse sélective de γ-amino acides cyclobutaniques : préparation de nouveaux organogélateurs peptidiques". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112365/document.
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L’acide γ-aminobutyrique ou GABA est le principal neurotransmetteur inhibiteur présent dans le système nerveux central (CNS). Afin d’obtenir un nouveau dérivé cyclobutanique du GABA, le cis-3,4CB-GABA, sous forme énantiomériquement pure, deux stratégies de synthèses efficaces et reproductibles ont été mises au point. Ces deux voies de synthèse impliquent toutes les deux une étape-clé de photocycloaddition [2+2] qui permet de créer le cycle à 4 chaînons. La première consiste en une homologation de l’acide cis-2-aminocyclobutanique (cis-ACBC), et la deuxième est une synthèse multi-étape qui utilise le caprolactame comme composé de départ.D’autre part, grâce à une synthèse stéréosélective du (1R,2S)-cis-2,3CB-GABA, quelques oligomères C- et N-protégés – di, tri, et tétra-peptides – de cet aminoacide ont été préparés. Ceux-ci ont été caractérisés par les techniques de RMN 1D et 2D, IR, RX. Les analyses ont montré qu’il n’existe pas d’interactions non-covalentes (liaisons hydrogène) inter-résidu au sein de ces structures moléculaires. En revanche, la propriété de gélification de ces oligomères dans différents solvants organiques a été mise en évidence. Des solutions et des gels formés à partir de ces peptides ont été analysés par microscope électronique à balayage et des clichés ont été obtenus montrant une organisation du dipeptide et du tetrapeptide en fibrilles. Le tripeptide lui n’a présenté aucun assemblage intermoléculaire régulierThe γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). In order to obtain new enantiomerically pure cyclobutanic derivative of GABA, the cis-3,4CB-GABA, two efficient synthetic strategies have been established. Both synthetic routes employed a photocycloaddition [2 +2] protocol, which provided the cyclobutanic ring. The first route involved the homolgation of the cis-2-aminocyclobutanecarboxylic acid (cis-ACBC), whereas the second route is a multi-step synthesis using caprolactam as starting material.On the other hand, the (1R,2S)-cis-GABA-2,3CB was synthetized, and a series of N- and C-protected oligomers of di, tri, and tetrapeptides of this amino acid were prepared. These oligomers were characterized by NMR (1D and 2D) techniques, IR, and X-ray. The analyses have shown that there are no non-covalent interactions (hydrogen bonds) between the residues of each oligomers. However, the gelation property of these oligomers in various organic solvents was demonstrated. Solutions and gels formed from these peptides were analyzed by scanning electron microscopy, and the obtained images showed a fibrous organization of the di- and tetrapeptide, while the tripeptide showed no regular intermolecular assembly
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Chami, Linda. "Étude de la production du peptide amyloïde dans la maladie d'Alzeimer : régulations transcriptionnelles de la βAPP et des β- et γ-sécrétases". Nice, 2012. http://www.theses.fr/2012NICE4065.
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La maladie d’Alzheimer se caractérise par des pertes de mémoire, des troubles cognitifs et une perte d’autonomie des patients. Les cerveaux des patients présentent des plaques séniles constituées principalement du peptide amyloïde (Aβ). Ce peptide contribue vraisemblablement à la dégénérescence des neurones observée dans la pathologie. Il est produit à partir de son précurseur la βAPP par deux activités enzymatiques, la β- puis la γ-sécrétase. L’activité β-sécrétase est portée par la protéine BACE1 tandis que la γ-sécrétase est un complexe protéique. Nous avons étudié la régulation transcriptionnelle des protéines impliquées dans la production d’Aβ car il constitue une cible thérapeutique importante. Le facteur de transcription NF-κB est activé dans la maladie d’Alzheimer. Nous avons montré que NF-κB affecte la production d’Aβ en réduisant la transcription de la βAPP et des β- et γ-sécrétases. Cette régulation est complexe car à des concentrations supraphysiologiques d’Aβ mimant les conditions pathologiques, NF-κB est activateur de la production du peptide amyloïde. Ces travaux suggèrent l’instauration d’un rétrocontrôle positif favorisant la production d’Aβ en conditions mimant la pathologie. La mort neuronale étant une caractéristique de la maladie d’Alzheimer, nous avons également étudié la régulation de la production d’Aβ par le facteur de transcription pro-apoptotique p53. Nos résultats préliminaires montrent que p53 inhibe la sécrétion d’Aβ. Enfin, dans le cadre de l’exploration du dialogue fonctionnel entre les deux sécrétases, nous montrons que le clivage γ-sécrétase des cadhérines épithéliale et neurale, ainsi que de Notch-1 régule la transcription de BACE1Alzheimer’s disease (AD) is characterized by memory loss, cognitive deficits and a loss of the patient’s autonomy. AD brains harbor senile plaques mainly composed of amyloid peptide (Aβ). This peptide likely contributes to the neurodegeneration. Aβ is produced by cleavage of its precursor βAPP by two enzymatic activities, the β- and the γ-secretase. Aβ is an important therapeutic target; we thus studied the transcriptionnal regulation of the proteins involved in its production. The transcription factor NF-κB is activated in Alzheimer’s disease. We show that NF-κB reduces Aβ production by inhibiting the transcription of βAPP and of the β- and γ-secretases. This regulation is complex, as in supraphysiological Aβ concentration, a condition close to the pathology, NF-κB is an activator of Aβ production. This suggests a positive feedback loop favoring Aβ production in pathological conditions. Neuronal death is characteristic of Alzheimer’s disease. We thus studied the regulation of Aβ production by the pro-apoptotic transcription factor p53. Our preliminary results indicate that p53 inhibits Aβ secretion. Finally we show a functional dialogue between the two secretases. Thus the γ-secretase cleavage of Notch-1 and of the epithelial and the neural cadherins regulates BACE1 transcription
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Bakir, Ilyas. "Molecular studies of the γ-secretase complex activity and selectivity towards the two substrates APP and Notch". Thesis, Mälardalen University, School of Sustainable Development of Society and Technology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-9622.
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Alzheimer Disease (AD) is the most common neurodegenerative disorder in the world. One of the neuropathological hallmarks of AD is the senile plaques in the brain. The plaques are mainly composed of the amyloid β (Aβ) peptide. Aβ is generated from the amyloid precursor protein, APP, when it is first cleaved by the β-secretase and subsequently the γ-secretase complex. The γ-secretase complex cleaves at different sites, called γ and ε, where the γ-cleavage site generates Aβ peptides of different lengths and ε-cleavage generates the APP intracellular domain (AICD). The two major forms of Aβ is 40 and 42 amino acids long peptides, where the latter is more prone to aggregate and is the main component in senile plaques. The γ-secretase complex is composed of four proteins; Pen-2, Aph-1, nicastrin and presenilin (PS). The PS protein harbours the catalytic site of the complex, where two aspartate residues in position 257 and 385 (Presenilin 1 numbering) are situated. Most Familial AD (FAD) mutations in the PS gene cause a change in the γ-cleavage site, leading to a shift from producing Aβ40 to the longer more toxic variant Aβ42. Frequently, this often leads to impairments of the AICD production. Another substrate for the γ-secretase complex is Notch. It is important to maintain the Notch signaling since an intracellular domain (NICD) is formed after cleavage by the γ-secretase complex in the membrane (S3-site) and this domain is involved in transcription of genes important for cell fate decisions.
It has been reported that certain APP luminal juxtamembrane mutations could drastically alter Aβ secretion, however their effect on AICD production remains unknown. In this study we want to analyse wether the juxtamembrane region is important for the AICD production. To gain more insight into the luminal juxtamembrane function for γ-secretase-dependent proteolysis, we have made a juxtamembrane chimeric construct. A four-residue sequence preceding the transmembrane domain (TMD) of APP (GSNK), was replaced by its topological counterpart from the human Notch1 receptor (PPAQ). The resulting chimeric vector C99GVP-PPAQ and the wildtype counterpart were expressed in cells lacking PS1 and PS2 (BD8) together with PS1wt. We observed that the chimeric construct did not alter production of AICD when using a cell based luciferase reporter gene assay monitoring AICD production. We also introduced a PS1 variant lacking a big portion of the large hydrophilic loop, PS1∆exon10, since our group has previously observed that this region affect Aβ production143. We found that the absence of the large hydrophilic loop in PS1 gave a 2-fold decrease in AICD-GVP formation from C99GVPwt compared to PS1wt. The activity of PS1wt and PS1Δexon10 using C99GVP-PPAQ as a substrate gave similar result as the C99GVPwt substrate, i.e. a 2-fold decrease in AICD-GVP formation when comparing PS1Δexon10 with PS1wt. From this data we therefore suggest that the four residues in the juxtramembrane domain (JMD) (GSNK) is not altering ε-cleavage of APP when changed to Notch1 counterpart, PPAQ. Furthermore, we also show that the 2-fold decrease in AICD-production by the PS1Δexon10 molecule is not changed between the two substrates C99GVPwt and C99GVP-PPAQ. This indicates that the luminal region of APP is not directly involved in the ε-site processing. If the luminal region is affecting processing in the γ-cleavage sites, remains however to be investigated.
Części książek na temat "Γ Peptide"
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Zerkout, S., M. P. Golinelli, V. Grand, J. Vidal, A. Collet, A. Aubry i M. Marraud. "Hydrazino peptide mimics of the γ- and β-turns". W Peptides 1994, 690–91. Dordrecht: Springer Netherlands, 1995. http://dx.doi.org/10.1007/978-94-011-1468-4_317.
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Nishiuchi, Yuji, Masayuki Nakao, Makoto Nakata i Shumpei Sakakibara. "Synthesis of γ-carboxyglutamic acid-containing peptides by Boc strategy using HF for final deprotection". W Peptide Chemistry 1992, 61–64. Dordrecht: Springer Netherlands, 1993. http://dx.doi.org/10.1007/978-94-011-1474-5_18.
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Fluhrer, Regina, i Christian Haass. "Intramembrane Proteolysis by γ-Secretase and Signal Peptide Peptidases". W Intracellular Traffic and Neurodegenerative Disorders, 11–26. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-87941-1_2.
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Bernatowicz, Michael S., Catherine E. Costello i Gary R. Matsueda. "Synthesis of an є-(γ-Glu) Lys cross-linked peptide in human fibrin". W Peptides, 187–88. Dordrecht: Springer Netherlands, 1988. http://dx.doi.org/10.1007/978-94-010-9595-2_53.
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Newlander, Kenneth A., James F. Callahan, Michael L. Moore, Thaddeus A. Tomaszek i William F. Huffman. "A novel constrained reduced-amide inhibitor of HIV-1 protease derived from the systematic incorporation of γ-turn mimetics into a model substrate". W Peptide Chemistry 1992, 535–37. Dordrecht: Springer Netherlands, 1993. http://dx.doi.org/10.1007/978-94-011-1474-5_156.
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Blumenstein, Michael, i Gary R. Matsueda. "Correlation of conformation with antibody affinity for fibrinogen γ-chain carboxyl terminal peptide segment". W Peptides, 237–38. Dordrecht: Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-011-2264-1_82.
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van Wickern, B., K. Kleeberg, D. Rogosch i H. Steinhart. "Determination of Γ-Radiation Induced Products in Free and Peptide Bound Tryptophan". W Advances in Experimental Medicine and Biology, 649–53. Boston, MA: Springer US, 1996. http://dx.doi.org/10.1007/978-1-4613-0381-7_105.
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Meister, Alton, Suresh S. Tate i Gregory A. Thompson. "On the Function of the γ-Glutamyl Cycle in the Transport of Amino Acids and Peptides". W Ciba Foundation Symposium 50 - Peptide Transport and Hydrolysis, 123–50. Chichester, UK: John Wiley & Sons, Ltd., 2008. http://dx.doi.org/10.1002/9780470720318.ch8.
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v.d. Muelbe, Florian, Thomas Mothes, Holm Uhlig, A. A. Osman, Toni Weinschenk, Dietmar G. Schmid, Günther Jung i Burkhard Fleckenstein. "Deamidation within a γ-Gliadin-Derived Peptide Enhances Its Recognition by Serum Antibodies of CD Patients". W Peptides: The Wave of the Future, 1037–38. Dordrecht: Springer Netherlands, 2001. http://dx.doi.org/10.1007/978-94-010-0464-0_485.
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Kuroda, Motonaka, i Naohiro Miyamura. "Effect of a Kokumi Peptide, γ-Glutamyl-Valyl-Glycine, on the Sensory Characteristics of Foods". W Koku in Food Science and Physiology, 85–133. Singapore: Springer Singapore, 2019. http://dx.doi.org/10.1007/978-981-13-8453-0_7.
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Fresslnaud, E., J. E. Sadler, J. P. Girma, H. R. Baumgartner i D. Meyer. "SYNTHETIC RGD-CONTAINING PEPTIDES OF VON WILLEBRAND FACTOR INHIBIT PLATELET ADHESION TO COLLAGEN". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643591.
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The Arg-Gly-Asp (RGD) sequence is common to fibrinogen (Fg), fibronectin (Fn) and von Willebrand Factor (vWF). RGD-containing peptides compete for binding of these adhesive proteins to platelet membrane GPIIb/IIIa and inhibit thrombin-induced platelet aggregation as does an unrelated dodecapeptide from the γ Fg COOH terminus (γFg 400-411). We compared in flowing blood the effect of γ Fg 400-411 and of 3 synthetic peptides derived from the sequence of human vWF upon platelet adhesion to collagen. The 3 vWF peptides (13 or 18 aminoacids) contained an RGD sequence in the NH2 (peptide 03), central (peptide 07) or COOH (peptide 02) portions. Collagen was coated onto plastic coverslips and exposed in a parallel-plate perfusion chamber to reconstituted human blood at a shear rate of 2,600 s™1 for 3 min at 37°C. Perfusates contained physiological concentrations of 51 Cr-platelets and red cells in either citrated autologous plasma or modified Tyrode buffer containing 4% human albumin ; in the latter case, the collagen-coated coverslips were preincubated with normal plasma or purified human vWF prior to perfusion. Platelet-collagen interactions were estimated by radioactivity counting and quantitative morphometry. RGD peptides 02, 03 and 07 inhibited platelet-collagen interactions in a dose-dependent manner. With peptide 07, deposition of 51 Cr-platelets decreased from 283.8 ± 32.5 × 105/cm2 (mean ± SEM, n = 3) with buffer to 169.6 ± 33.0 in the presence of 50 μM peptide (p < 0.05), 133.7 ± 26.4 with 150 uM (p <0.012) and 101.8 ± 27.1 with 300 uM (p <0.005). The inhibitory effect of γ Fg 400-411 upon platelet deposition was less significant than that of the RGD peptides at 50 and 150 uM concentrations (224.4 ± 39.8, N.S. and 139.5 ± 55.3, p < 0.05, respectively). RGD peptide 07 also inhibited in a dose-dependent way both platelet adhesion to collagen and thrombus growth. Similar results were observed with peptides 02 and 03, indicating that the position of the RGD sequence is not critical. No synergetic effect between RGD and γFg 400-411 peptides was observed. These results with vWF peptides confirm that GPIIb/IIIa is involved not only In platelet aggregation (thrombus growth) but also in vWF-mediated platelet adhesion to collagen.
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Lam, S., E. F. Plow, A. L. Frelinger III, M. A. Smith, J. C. Loftus i M. H. Ginsberg. "ARG-GLY-ASP (RGD) PEPTIDES INCREASE THE EXPOSURE OF THE CARBOXYL TERMINAL REGION OF THE HEAVY CHAIN OF GPIIB ON THE PLATELET SURFACE". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643698.
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RGD peptides and those derived from the fibrinogen γ chain (e.g., γ 400-411 (H12)) are inhibitors of platelet aggregation and fibrinogen binding. These two sets of peptides interact with a common adhesive protein receptor on platelets which contains GPIIb-IIIa (JBC, 262:947, 1987). A 17 amino acid sequence near the carboxyl terminus of GPIIbα recognized by the PMI-1 monoclonal antibody (JCI, 78:1103, 1986), isexpressed on the cell surface under certain conditions which are not permissive for fibrinogen binding. Thus, achange in the surface orientation of GPIIb is associated with inhibitionofplatelet aggregation and fibrinogen binding. To investigate whether or notsuch changes in GPIIb-IIIa occur during peptide inhibition of plateletfunction, we examined peptide effectson exposure of the PMI-1 epitope. Three different RGD peptides induced reversibly increased binding of 125I-PMI-1 to both resting and thrombin-stimulated platelets. Specificity of this effect was demonstrated bythe failure of the inactive peptides GRGESP andSDGR to induce PMI-1 binding. This effect does not appear to requireviable platelets since it was observed on fixed cells and in detergent solutioncontaining purified GPIIb-IIIa. Theγchair, peptides provoked asimilar effect, but required greater concentrations than the RGD peptides.These results indicate that RGDpeptides, in addition to their presumed competitive effect on adhesive protein binding to platelets, are also capableof increasing the surface exposureofthe carboxyl terminus of the heavy chain of GPIIb, thus potentially altering platelet function.
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D’Souza, S. E., M. H. Ginaberg, S. Lam i E. A. Plow. "ACTIVATION DEPENDENT ALTERATIONS IN THE CHEMICAL CROSSLINKING OF ARGINYL-GLYCYL-ASPARTIC ACID (RGD) PEPTIDES WITH PLATELET GLYCOPROTEIN (GP) GPIIb-IIIa". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643699.
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The platelet adhesive proteins, fibrinogen, fibronectin and von WillebrandFactor, contain RGD amino acid sequences; RGD-containing peptides inhibit the binding of these adhesive proteins to platelets; and a membrane receptor for these adhesive proteins binds to Arg-Gly-Asp and contains GPIIb-IIIa. The present study was undertaken to characterize the interaction of RGDpeptides with GPIIb-IIIa using a chemical crosslinking approach. A radioiodinated RGD-containing heptapeptide was bound to washed human platelets under conditions at which ≥ 85% of theinteraction was inhibited by excess nonlabeled peptide. After binding of the peptide to platelets for 45 min at22°, a homobifunctional crosslinking reagent was added, and the platelets were extracted and analyzed on polyacrylamide gels. With resting platelets,autoradiography of the gels revealedthat the peptide crosslinked tobothGPIIb and GPIIIa. This interaction wasinhibited by excess nonlabeled peptide but not by certain conservatively substituted RGD peptides. Stimulation of the platelets caused a dramatic increase in crosslinking of the peptide to only one of the two subunitsof GPIIb-IIIa. The stimulus dependentincrease in the crosslinking reactionwas specific and saturable as it was inhibited by RGD peptides in a dose dependent manner. In addition, peptides corresponding in structure to the carboxy terminus of the γ chain of fibrinogen also produced concentration dependent inhibition of the interaction. The increase in crosslinking induced by platelet stimulation was divalent ion dependent. Similar results werealso obtained with a second, larger RGD-containing peptide and with asecond chemical crosslinking reagent.Theseresults indicate that platelet stimulation in the presence of divalent ions causes a change which permitsmoreefficient crosslinking of RGD-containing peptides to only one of the two subunits of GPIIb-IIIa. The results are also compatible with a proximalrelationship of both subunits tothe RGD binding sites on the plateletmembrane.
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Cierniewski, C. S., i A. Z. Budzynski. "CONFORMATIONAL EQUILIBRIA IN THE γ CHAIN COOH-TERMINUS OF HUMAN FIBRINOGEN". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642935.
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Synthetic peptides and fragments cleaved from native fibrinogen are used in studies to localize binding sites for various ligands. We addressed the question how the native conformation of a selected γ chain segment is affected by scission of the original chain. The conformation of the γ chain COOH-terminus of intact fibrinogen and its various fragments containing this region has been compared by an immunochemical analysis. An antibody population specific for the native epitope within the γ391-405 segment was isolated by affinity chromatography on the corresponding synthetic peptide. Between 19.2 and 22.8% of antibodies were obtained from three different antisera indicating that this region represents one of the major epitopes of native fibrinogen. Anti-γ391-405 antibodies were used to determine the value of Kconf the equilibrium constant for the interconversion of the non-native and native conformations of this epitope. The measurements were done using native fibrinogen, fragments D1 and DD, γ chain and γ391-405 synthetic peptide. In addition, the effect of 5 M guanidine-HCl on the conformation of fragments D1 and DD, which is known to abolish their antipolymerizing activity, was studied. Radioiodinated fibrinogen was used in the determination of Kconf, and quantitative analytical parameters, CI50% and CIs, calculated from competition between 125I-fibrinogen and the fibrinogen derivatives under study for binding to the immunochemically purified antibody. The measurements indicated that the epitope is unperturbed by iodination of fibrinogen and that 38.3% of fragment D1, 8.9% of fragment DD, 3.6% of the γ chain and less than 0.008% of the γ391-405 molecules adopt in aqueous solution the native conformation within the epitope. Denaturation of fragment D1 with 5 M guanidine-HCl affected only slightly the conformation of this γ chain determinant. More significant changes in the conformation were observed when fragment DD was denatured. The results suggest that long-range interactions are necessary for the stabilization of the native structure in the region of fibrinogen that interacts with the antibody and which is in close vicinity to the polymerization site, crosslinking site, and platelet recognition site.
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Terukina, S., M. Matsuda, N. Yoshida, K. Yamazumi, Y. Takeda i T. Takano. "TWO ABNORMAL FIBRINOGENS DESIGNATED AS OSAKA II AND MORIOKA WITH A HITHERTO UNIDENTIFIED AMINO ACID SUBSTITUTION; γARG-275 BY CYS". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644701.
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A hitherto unidentified amino acid substitution of γ Arg-275 by Cys has been found in two abnormal fibrinogens, Osaka II and Morioka. The propositi are both asymptomatic heterozygotes for the abnormality characterized by altered polymerization of fibrin monomers. Reducing SDS-PAGE revealed that fibrinogens derived from thé propositi both consist of two populations; one with a normal and the other with an abnormal longer γ-chain by 0.5 Kd.The γ-γ cross-linking took place nearly normally, however. Analyzing plasmic digests of fibrinogen by SDS-PAGE, we located the abnormality residing in the γ-chain remnant of fragment D. Chromatofocusing of D1 obtained by plasmic digestion in 5 mM Ca++ of purified fibrinogen separated the variant D1 (vD1) from the normal one (nD1) distinctly, as confirmed by SDS-PAGE and functional studies. As anticipated, vD1 failed to interfere with normal fibrin polymerization and thrombin clotting of normal fibrinogen, whereas nD1 inhibited these reactions significantly. After reduction and pyridylethylation, vD1 and nD1 were individually digested with lysylendopeptidase (lysEP). Analyzing the digests by reverse phase HPLC, we noted a single peak present in the digests of vD1 but missing in those of nD1, and vice versa. Analysis of N-terminal five cycles of these peptides suggested that both of them corresponded to the peptide with residues 274302 based on the known sequence data. Primary sequence and total amino acid analyses revealed that γ Arg-275 has been substituted by Cys in both of these abnormal fibrinogens. Analysis of the lysEP-digests of the isolated γ-chain also gave the same result. Since no free SH has been identified at the γ Cys-275 substitute, the variant γ-chain may be endowed with some additive by an S-S linkage. Even if so, elucidation of an apparent elongation by SDS-PAGE of the γ-chain variant must await further investigation. In any case, however, the substitution of γ Arg-275 by Cys may have induced critical alterations in the γ-chain-dependent polymerization site in the D domain in these two abnormal fibrinogens.
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Wilhelm, S., i A. Henschen. "ON THE IDENTIFICATION OF POLYMORPHIC SITES IN HUMAN FIBRINOGEN PEPTIDE CHAINS". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643327.
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Human fibrinogen has repeatedly been shown to occur in a great number of different molecular forms. Some types of heterogeneity are evident already from variations in solubility properties and in ion-exchange-chromatographic as well as gel-electrophoretic behaviour of the total molecule and of its peptide chain components. The reason for these variations are partly known.Thus, degradation of the C-terminal parts and phosphorylation of two serine residues gives rise to heterogeneity in the Aα-chain. Differences in the sialylation of the carbohydrate side chain causes heterogeneity both in the Bβ- and the γ-chain. Differences in chain length at the C-terminus of the γ-chain are responsible for additional variation. All these variants are expected to exist in each human being. An other category of human fibrinogen variants may be due to genetic polymorphism within the population, i.e. the presence of inherited, common, normal variants. Seven sites of microheterogeneity have so far been tentatively identified, mainly by disagreements between protein and DNA sequence analyses. Three of the sites are located in the Aα-chain (positions 47, 296 and 312), three in the Bβ-chain (positions 162, 296 and 44-8) and one in the γ-chain (position 88). The aim of the present study was to identify these sites on the proteinchemical level in pooled plasma as well as in plasma from single individuals, especially various members of the same family. For this purpose suitable fibrinogen fragments containing the tentatively microheterogeneous sites were isolated after cleavage of fibrinogen with cyanogen bromide, trypsin and/or chymotrypsin by repeated fractionations by means of conventional and reversed-phase high-performance liquid chromatography and counter-current distribution. The components were characterized by N-terminal sequence and amino acid composition. Polymorphism in human fibrinogen has previously only once been identified by restriction fragment length analysis in a non-transcribed region of the Aα-chain locus but never in the transcribed regions, i.e. the peptide chains.The present investigation will allow the estimation of the number of peptide chain haplotypes and their possible correlation to other genetic variants of fibrinogen.
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Charon, M. H., L. Tranqui, A. Andrieux, G. Hudry-Clergeon i G. Marguerie. "FIBRINOGEN BINDING TO ENDOTHELIAL CELLS AND INTERFERING PEPTIDES". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644735.
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Fibrinogen interacts with platelets and endothelial cells via specific binding sites. While the platelet fibrinogen receptor has been identified and was found to be associated with GPIIb-IIIa, the binding site on endothelial cells has not been characterized yet. The platelet GPIIb-IIIa belongs to the newly identified cytoadhesin family which includes immunologicaly related receptors interacting with RGD containing proteins. A cytoadhesin has recently been described on endothelial cells and the possibility that fibrinogen might interact with this glycoprotein was examined. Peptides corresponding to γ and α chains sequences were synthesized and their capacity to inhibit fibrinogen binding to endothelial cells and platelets were compared. Analogues of the γ chain from His 400 to Val 411 produced an inhibition similar to that observed for fibrinogen platelet interaction, suggesting that the structure function relationship of γ peptides is identical in both systems. In contrast synthetic analogues corresponding to the a chain and including RGD yielded slightly different results. While RGD alone was inactive on platelet, this tripeptide was active on endothelial cells. RGDS and RGDF corresponding to α 572-575 and α 95-98 partially or fully inhibited fibrinogen binding to endothelial cells but the structure activity relationship was different when compared to that observed for platelets. Addition of the N and C sequences adjacent to RGDS reduced the activity of this peptide whereas the activity of RGDF analogues was not modified by addition of N and C-sequences. In contrast platelet fibrinogen binding decreased with these RGDF analogues. These results suggest that fibrinogen endothelial cell binding is mediated by an RGD adhesion receptor with subtle differences in the recognition selectivity of the ligand, which is controled by the surrounding sequence.
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Suttie, W. J., A. Cheung i M. G. Wood. "ENZYMOLOGY OF THE VITAMIN K-DEPENDENT CARBOXYLASE: CURRENT STATUS". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643991.
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The vitamin K-dependent microsomal carboxylase converts glutamyl residues in precursor proteins to γ-carboxyglutamyl (Gla) residues in completed proteins. The enzyme activity is present in significant activities in most non-skeletal tissues but has been studied most extensively in rat and bovine liver. Early studies of the enzyme utilized bound precursors of vitamin K-dependent clotting factors as substrates for the enzyme and demonstrated that the enzyme requires the reduced form of vitamin K (vitamin KH2), O2, and CO2. Subsequent investigations have taken advantage of the observation that the enzyme will carboxylate low-molecular-weight peptide substrates with Glu-Glu sequences. Utilizing a substrate such as Phe-Leu-Glu-Glu-Leu, it has been possible to demonstrate that γ-C-H release from the Glu residue of a substrate is independent of CO2 concentration. The formation of vitamin K 2,3-epoxide can also be demonstrated in a crude microsomal system, and it can be shown that the formation of this metabolite can be stimulated by the presence of a peptide substrate of the carboxylase. These observations have led to the general hypothesis that the mechanism of action of the enzyme involves interaction of vitamin KH2 with O2 to form an oxygenated intermediate that can interact with a substrate Glu residue to abstract a γ-hydrogen and in the process he converted to vitamin K epoxide (KO). The current evidence suggests that, either directly or indirectly, removal of the γ-C-H results in the formation of a carbanion at the γ-position of the Glu residue which can interact with CO2 to form Gla. The Glu residue intermediate which is formed can be demonstrated to partition between accepting a proton in the media to reform Glu, or interacting with CO2 to form Gla. Current data do not distinguish between the direct formation of a carbanion coupled to proton removal, or the participation of a reduced intermediate. Recent studies have demonstrated that the enzyme will carry out a partial reaction, the formation of vitamin K epoxide, at a decreased rate in the absence of a Glu site substrate. Epoxide formation under these conditions has the same for O2 as the carboxylation reaction and is inhibited in the same manner as the carboxylation reaction. In the presence of saturating concentrations of a Glu site substrate and C02, the ratio of KO formed, γ-C-H released, and C02 formed is 1:1:1. However, KO formation can be uncoupled from and proceeds at a higher rate than γ-C-H bond cleavage and Gla formation at low Glu site substrate concentrations. At saturating concentrations of CO2, Gla formation is equivalent to γ-C-H bond cleavage, and this unity is not altered by variations in vitamin KH2 or peptide substrate concentrations. Natural compounds with vitamin K activity are 2-Me-l,4-naphthoquinones with a polyprenyl side chain at the 3-position. Studies of vitamin K analogs have demonstrated that a 2-Me group is essential for activity but that the group at the 3-position can vary significantly. Modification of the aromatic ring of the naphthoquinone nucleus by methyl group substitution can result in alterations of either the rate of the carboxylation reaction or the apparent affinity of the enzyme for the vitamin. Studies of a large number of peptide substrates have failed to reveal any unique primary amino acid sequence which is a signal for carboxylation. However, current evidence from a number of sources suggests that a basic amino acid rich "propeptide" region of the intracellular form of the vitamin K-dependent proteins is an essential recognition site for the enzyme. This region of the precursor is lost in subsequent processing, and the manner in which it directs this posttranslational event is not yet clarified. Supported by NIH grant AM-14881.
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Kuyas, C., H. Sigrist i P. W. Straub. "LOCALIZATION CF FIBRIN POLYMERIZATION SITES BY PHOTQAFFINITY LABELING". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643776.
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Fibrin polymerization is competitively inhibited by the te-trapeptide GlyProArgPro. This peptide corresponds to the N-terminal sequence of the fibrin α-polypeptide chain, which is exposed upon release of fibrinopeptide A by thrombin. A binding site for GlyProArgPro was suggested to be located in the C-terminal end of the 411 amino acids containing γ-chain (Varadi and Scheraga, Biochemistry, 25, 519, 1986). In order to characterize the polymerization domain, GlyProArgProLys-azidoazobenzene, a photoactivable derivative of GlyProArgPro was synthesized. Photoaffinity label was bound to fibrinogen in the dark and photolysis was carried out at 0°C. After reduction and S-carboxymethy-lation of the photoaffinity labeled fibrinogen, the polypeptide chains (Aα, Bβ,γ ) were separated by ion-exchange chromatography. Photolabel binding was monitored imnunologically with anti-azo-benzene antibodies (ELISA, Western blot). Selective labeling of the γ-chain was observed. Labeled γ-chains were further digested with CNBr, and the resulting fragments were separated by reversed phase HPIC, immunologically characterized and identified by Edman degradation. GlyProArgProLys-azidoazobenzene was incorporated in the 18 kD CNBr-fragment (γ95-264). The CNBr-fragments arising from C-terminal end of the γ-chain were not labeled.Our results indicate that the binding site of GlyProArgPro is localized exclusively on γ-chain, within the sequence γ95-264.
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Hantgan, R. R. "LOCALIZATION OF THE DOMAINS OF FIBRIN INVOLVED IN BINDING TO PLATELETS". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643773.
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The molecular basis of platelet-fibrin interactions has been investigated by using synthetic peptides as potential inhibitors of binding fibrin protofibrils and fibrinogen to ADP-stimulated platelets, adhesion of fibrin fibers to the platelet surface, and platelet-mediated clot retraction. Synthetic peptides RGDS and HHLGGAKQAGDV, corresponding to regions of the fibrinogen α and γ chains previously identified as platelet recognition sites, inhibited the binding of radiolabelled soluble fibrin oligomers to ADP-stimulated platelets with IC50 values of 12 and 40 μM, respectively. The IC50 values obtained with fibrinogen as the ligand were 3-fold higher. Synthetic GPRP and GHRP, corresponding to the N-terminal sequences of the fibrin α and β chains, were minimally effective in blocking soluble fibrin oligomer binding to ADP-stimulated platelets. The extent of fibrin:platelet adhesion was determined with a microfluorimetric technique which measures the quantity of fluorescein-labelled fibrin attached to the surface of platelets. The signal obtained from the brightly fluorescent platelet:fibrin adducts was time- and concentration-dependent, and was fully inhibited by a monoclonal antibody directed against the glycoprotein II:IIIa complex (HP1-1D, kindly provided by Dr. W. Nichols). Inhibition of fibrin:platelet adhesion by RGDS, HHGGAKQAGDV, and GHRP all exhibited a similar, linear dependence on the peptide concentration, reaching 1/2 maximum at about 200 μM, suggesting nonspecific effects. GPRP inhibited fibrin assembly but did not appear to have specific effects on fibrin:platelet adhesion. The time course of clot retraction was followed by right angle light scattering intensity measurements. Only RGDS affected clot retraction, causing a 4-fold decrease in rate at 230 μM. These results indicate that fibrinogen and fibrin protofibrils, which are obligatory intermediates in the fibrin assembly pathway, share a set of common platelet recognition sites located at specific regions of the α and γ chains of the multinodular fibrin(ogen) molecules. The RGDS site is also involved in mediating interactions between the three dimensional fibrin network and ADP-stimulated platelets.
Raporty organizacyjne na temat "Γ Peptide"
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Baszler, Timothy, Igor Savitsky, Christopher Davies, Lauren Staska i Varda Shkap. Identification of bovine Neospora caninum cytotoxic T-lymphocyte epitopes for development of peptide-based vaccine. United States Department of Agriculture, marzec 2006. http://dx.doi.org/10.32747/2006.7695592.bard.
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The goal of the one-year feasibility study was to identify specific cytotoxic T-lymphocyte (CTL) epitopes to Neosporacaninum in the natural bovine host in order to make progress toward developing an effective peptide-based vaccine against bovine neosporosis. We tested the hypothesis that: N. caninum SRS2 peptides contain immunogenicCTLepitope clusters cross-presented by multiple bovine MHC-I and MHC-IIhaplotypes. The specific objectives were: (1) Map bovine CTLepitopes of N. caninum NcSRS-2 and identify consensus MHC-I and class-II binding motifs; and (2) Determine if subunit immunization with peptides containing N. caninum-specificCTLepitopes cross-reactive to multiple bovine MHChaplotypes induces a CTL response in cattle with disparate MHChaplotypes. Neosporosis is a major cause of infectious abortion and congenital disease in cattle, persisting in cattle herds via vertical transmission.5 N. caninum abortions are reported in Israel; a serological survey of 52 Israeli dairy herds with reported abortions indicated a 31% infection rate in cows and 16% infection rate in aborted fetuses.9,14 Broad economic loss due to bovine neosporosis is estimated at $35,000,000 per year in California, USA, and $100,000,000 (Australian) per year in Australia and New Zealand.13 Per herd losses in a Canadian herd of 50 cattle are estimated more conservatively at $2,305 (Canadian) annually.4 Up to date practical measures to reduce losses from neosporosis in cattle have not been achieved. There is no chemotherapy available and, although progress has been made toward understanding immunity to Neospora infections, no efficacious vaccine is available to limit outbreaks or prevent abortions. Vaccine development to prevent N. caninum abortion and congenital infection remains a high research priority. To this end, our research group has over the past decade: 1) Identified the importance of T-lymphocyte-mediated immunity, particularly IFN-γ responses, as necessary for immune protection to congenital neosporosis in mice,1,2,10,11 and 2) Identified MHC class II restricted CD4+ CTL in Neosporainfected Holstein cattle,16 and 3) Identified NcSRS2 as a highly conserved surface protein associated with immunity to Neospora infections in mice and cattle.7,8,15 In this BARD-funded 12 month feasibility study, we continued our study of Neospora immunity in cattle and successfully completed T-lymphocyte epitope mapping of NcSRS2 surface protein with peptides and bovine immune cells,15 fulfilling objective 1. We also documented the importance of immune responses NcSRS2 by showing that immunization with native NcSRS2 reduces congenital Neospora transmission in mice,7 and that antibodies to NcSRS2 specifically inhibition invasion of placental trophoblasts.8 Most importantly we showed that T-lymphocyte responses similar to parasite infection, namely induction of activated IFN-γ secreting Tlymphocytes, could be induced by subunit immunization with NcSRS2 peptides containing the Neospora-specificCTLepitopes (Baszler et al, In preparation) fulfilling objective 2. Both DNA and peptide-based subunit approaches were tested. Only lipopeptide-based NcSRS2 subunits, modified with N-terminal linked palmitic acid to enhance Toll-like receptors 2 and 1 (TLR2-TLR1), stimulated robust antigen-specific T-lymphocyte proliferation, IFN-γ secretion, and serum antibody production across different MHC-IIhaplotypes. The discovery of MHC-II cross-reactive T-cellinducing parasite peptides capable of inducing a potentially protective immune response following subunit immunization in cattle is of significant practical importance to vaccine development to bovine neosporosis. In addition, our findings are more widely applicable in future investigations of protective T-cell, subunit-based immunity against other infectious diseases in outbred cattle populations.