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Artykuły w czasopismach na temat "Γ-peptides"
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Bracci, Laura, David F. Stroncek, Stefanie Slezak, Giulio C. Spagnoli i Maurizio Provenzano. "Comprehensive Analysis of CD8 T Cell Immune Response Specific for Two Novel HLA-A*0201 Restriced CMV pp65 Peptides." Blood 106, nr 11 (16.11.2005): 3928. http://dx.doi.org/10.1182/blood.v106.11.3928.3928.
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Abstract In immune compromised subjects such as patients undergoing bone marrow, organ transplantation or immunosuppressive therapies, Cytomegalovirus (CMV) infection is associated with significant morbidity until the individual’s immune system is completely reconstituted. One method of preventing CMV infection during immune suppression in transplant patients is represented by adoptive administration of CMV peptide-specific cytotoxic T lymphocytes (CTLs) from HLA-matched donors. Despite the strong immunogenicity demonstrated by specific HLA class I peptides, the peptide’s responsiveness varies among individuals. Therefore, it is important to identify additional epitopes for each HLA determinant of interest. In this study we report a comprehensive analysis of CD8 T cell-specific activity against two novel CMV pp65 HLA-A*0201 associated peptides in CMV-experienced HLA-A*0201 subjects. PBMCs from CMV seropositive HLA-A*0201 restricted healthy subjects were peptide-stimulated ex vivo and IFN-γ gene expression was analyzed by qrt-PCR. An IFN-γ ELISPOT assay was carried out on peptide-specific elicited CD8 T lymphocytes to confirm the qrt-PCR results. Tetrameric HLA/epitope complexes (tHLA) were used to track the levels of peptide-specific CD8 T cells responsiveness to cognate epitopes. In addition, in vitro peptide-specific expanded populations of CTLs were used in 51Cr release assay. Based on qrt-PCR results, four out of eight HLA-A*0201 peptides identified by computer algorithms were selected. Two are preaviously published peptides: pp65495–503 (NLVPMVATV) and pp65347–355 (ALFFFDIDL), while two are novel: pp65340–348 (RQYDPVAAL) and pp65310–318 (LMNGQQIFL). In spite the four peptides induced comparable mRNA IFN-γ transcript production, peptides pp65495–503, pp65340–348 and pp65310–318 induced a consistent and sustained IFN-γ protein release and specific killing, while the pp65347–355 failed to induce IFN-γ protein secretion and killing activity (if we exclude a positive IFN-γ protein release after 2-week in vitro induction in one of the donors tested). Comparative assays carried on the functional activity of the three peptides pp65495–503, pp65340–348 and pp65310–318 revealed no intrinsic differences in term of IFN-γ protein release and cytotoxic activity save for the CTL affinity to the HLA-A*0201/epitope complexes (pp65495–503 ~2.6% in nearly 100% of donors vs pp65340–348 ~0.67% or pp65310–318 ~0.77% in nearly one third of the donors after 2-week in vitro induction). The tHLA binding results could be possibly ascribed to differencies in the peptide avidity and stability for the HLA class I. Taken together, these results lead to the conclusion that different peptides can induce a variable levels of immune responses ranging between mere cytokine gene expression and effective cytotoxic activity. In addition, the two novel peptides selected here broaden the panel of potential reagents useful for adoptive immune therapy. Thus, in anticipation of a specific epitope-targeted immune intervention, the three HLA-A*0201 peptides described could be used in combination for adoptive transfer of epitope-specific T cells or epitope-specific vaccination.
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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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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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Saini, Chaman, H. K. Prasad, Rajni Rani, A. Murtaza, Namita Misra, N. P. Shanker Narayan i Indira Nath. "Lsr2 of Mycobacterium leprae and Its Synthetic Peptides Elicit Restitution of T Cell Responses in Erythema Nodosum Leprosum and Reversal Reactions in Patients with Lepromatous Leprosy". Clinical and Vaccine Immunology 20, nr 5 (27.02.2013): 673–82. http://dx.doi.org/10.1128/cvi.00762-12.
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ABSTRACTThe Lsr2 protein ofMycobacterium lepraeand its synthetic peptides have been shown to elicit lymphoproliferation and gamma interferon (IFN-γ) release by peripheral blood mononuclear cells (PBMCs) of patients with lepromatous leprosy (M. Chaduvula, A. Murtaza, N. Misra, N. P. Narayan, V. Ramesh, H. K. Prasad, R. Rani, R. K. Chinnadurai, I. Nath, Infect. Immun. 80:742–752, 2012). PBMCs from 16 patients with lepromatous leprosy who were undergoing erythema nodosum leprosum (ENL) (type 2) and 5 patients with reversal reactions (RR) (type 1) were stimulated withM. leprae, recombinant Lsr2, and six end-to-end synthetic peptides (A through F) spanning the Lsr2 sequence. During the reaction all patients with ENL showed lymphoproliferation (stimulation index, >2) in response to peptides A and F, with other peptides eliciting responses in 75 to 88% of the subjects. In PBMC cultures, both lymphoproliferation and IFN-γ release for peptide E were significantly higher than for peptides B and C and recombinant Lsr2 (P< 0.05, Wilcoxon signed-rank test). Five patients with RR also showed enhanced lymphoproliferative responses and IFN-γ release in response to Lsr2,M. leprae, and peptide E. Six months postreaction, 14 patients with ENL continued to exhibit responses to Lsr2 and its peptides, with the highest responses being elicited by peptide E. However, 5 subjects showed no lymphoproliferation and had reduced IFN-γ release in response to Lsr2 peptides (P< 0.001, Kruskal-Wallis test) but responded to recombinant Lsr2. Six patients with ENL had HLA-A*68.01, which the STFPEITHI program showed to have high peptide-binding scores of 20 to 21 for peptides E, B, and C. Eleven patients had HLA-DRB1*1501 and HLA-DRB1*1502, which had high binding scores for peptides C and E. Thus, Lsr2 and its peptides are recognized in leprosy reactions during and well after the subsidence of clinical signs.
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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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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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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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BECERRIL, Baltazar, Miguel CORONA, Fredy I. V. CORONAS, Fernando ZAMUDIO, Emma S. CALDERONARANDA, Paul L. FLETCHER, Brian M. MARTIN i Lourival D. POSSANI. "Toxic peptides and genes encoding toxin γ of the Brazilian scorpions Tityus bahiensis and Tityus stigmurus". Biochemical Journal 313, nr 3 (1.02.1996): 753–60. http://dx.doi.org/10.1042/bj3130753.
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Seven toxic peptides from the venom of Tityus bahiensis and Tityus stigmurus were isolated and sequenced, five of them to completion. The most abundant peptide from each of these two species of scorpion was 95% identical with that of toxin γ from the venom of Tityus serrulatus. They were consequently named γ-b and γ-st respectively. The genes encoding these new γ-like peptides were cloned and sequenced by utilizing oligonucleotides synthesized according to known cDNA sequences of toxin γ, and amplified by PCR on templates of DNA purified from both T. bahiensis and T. stigmurus. They contain an intron of approx. 470 bp. Possible mechanisms of processing and expressing these peptides are discussed, in view of the fact that glycine is the first residue of the N-terminal sequence of T. stigmurus, whereas lysine is the residue at position 1 of toxin γ from T. serrulatus and T. bahiensis. In addition, chemical characterization of the less abundant toxic peptides showed the presence of at least four distinct families of peptides in all three species of the genus Tityus studied. There is a large degree of similarity among peptides from different venoms of the same family. By using specific horse and rabbit antisera, the venoms of T. bahiensis, T. serrulatus and T. stigmurus were compared. They showed an extended degree of cross-reactivity. Thus these three species of scorpion have similar toxic components, the genes of which are similarly organized, processed and expressed.
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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.
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Staska, Lauren M., Christopher J. Davies, Wendy C. Brown, Travis C. McGuire, Carlos E. Suarez, Joo Youn Park, Bruce A. Mathison, Jeffrey R. Abbott i Timothy V. Baszler. "Identification of Vaccine Candidate Peptides in the NcSRS2 Surface Protein of Neospora caninum by Using CD4+ Cytotoxic T Lymphocytes and Gamma Interferon-Secreting T Lymphocytes of Infected Holstein Cattle". Infection and Immunity 73, nr 3 (marzec 2005): 1321–29. http://dx.doi.org/10.1128/iai.73.3.1321-1329.2005.
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ABSTRACT Previously, our laboratory showed that Holstein cattle experimentally infected with Neospora caninum develop parasite-specific CD4+ cytotoxic T lymphocytes (CTL) that lyse infected, autologous target cells through a perforin-granzyme pathway. To identify specific parasite antigens inducing bovine CTL and helper T-lymphocyte responses for vaccine development against bovine neosporosis, the tachyzoite major surface proteins NcSAG1 and NcSRS2 were targeted. In whole tachyzoite antigen-expanded bovine T-lymphocyte lines, recombinant NcSRS2 induced potent memory CD4+- and CD8+-T-lymphocyte activation, as indicated by proliferation and gamma interferon (IFN-γ) secretion, while recombinant NcSAG1 induced a minimal memory response. Subsequently, T-lymphocyte epitope-bearing peptides of NcSRS2 were mapped by using overlapping peptides covering the entire NcSRS2 sequence. Four experimentally infected cattle with six different major histocompatibility complex (MHC) class II haplotypes were the source of immune cells used to identify NcSRS2 peptides presented by Holstein MHC haplotypes. NcSRS2 peptides were mapped by using IFN-γ secretion by rNcSRS2-stimulated, short-term T-lymphocyte cell lines, IFN-γ enzyme-linked immunospot (ELISPOT) assay with peripheral blood mononuclear cells, and 51Cr release cytotoxicity assay of rNcSRS2-stimulated effector cells. Four N. caninum-infected Holstein cattle developed NcSRS2 peptide-specific T lymphocytes detected ex vivo in peripheral blood by IFN-γ ELISPOT and in vitro by measuring T-lymphocyte IFN-γ production and cytotoxicity. An immunodominant region of NcSRS2 spanning amino acids 133 to 155 was recognized by CD4+ T lymphocytes from the four cattle. These findings support investigation of subunit N. caninum vaccines incorporating NcSRS2 gene sequences or peptides for induction of NcSRS2 peptide-specific CTL and IFN-γ-secreting T lymphocytes in cattle with varied MHC genotypes.
Rozprawy doktorskie na temat "Γ-peptides"
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Qureshi, Muhammad Khurram Naseem. "Foldamers based on γ-peptides". Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611289.
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Stanovych, Andrii. "Synthèse et études structurales de γ-peptides synthétisés à partir d’acides β,γ-diaminés". Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112310/document.
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L’élaboration de nouveaux oligomères capables de mimer les propriétés des protéines naturelles est devenue un domaine de recherche très important, non seulement du point de vue structural mais aussi médicinal. Les peptides comportant des acides β-aminés ont été extensivement étudiés tandis que les recherches dans le domaine des γ-peptides sont plus récentes. Néanmoins, ces derniers montrent déjà des propriétés structurales uniques ainsi que des activités biologiques prometteuses.Dans notre laboratoire nous nous intéressons au développement d’une synthèse générale de nouveaux acides β,γ-diaminés à partir d’acides ∝-aminés naturels, notamment à la 3-déoxyaminostatine, et à leur utilisation dans la synthèse peptidique pour obtenir des peptides non-naturels afin d’étudier leurs propriétés conformationnelles. La stratégie de synthèse élaborée dans notre laboratoire et améliorée au cours de ces travaux a permis d’élargir la gamme des acides β,γ-diaminés. Deux diastéréomères cis et trans issus de la L-leucine, de la L- et D-phénylalanine ont été obtenus et engagés dans la synthèse de nouveaux peptides hybrides α/γ. Deux séries de peptides hybrides α/γ ont été étudiées. Les analyses structurales de la série comportant des acides ∝-aminés de configuration L montrent une capacité à adopter des structures secondaires bien définies, stabilisées par des liaisons hydrogènes intramoléculaires, impliquant notamment l’azote situé en β. De plus, une voie de synthèse vers un analogue d’un antibiotique naturel, le gramicidine S, a été proposée. Dans cet analogue, le motif D-Phe-L-Pro est remplacé par l’acide β,γ-diaminé issu de la D-phénylalanineThe design of a new oligopeptides, capable to mimic the properties of natural proteins, is an important field not only for structural studies but also in the developpement of new efficient drugs. The peptides featuring β-amino acids have been extensively explored, whereas the research in γ-peptides is more recent. The studies of γ-peptides show their ability to adopt stable secondary structures and also to have a promising biological activity. Our laboratory is interested in the synthesis of new β,γ-diaminoacids.The aim of this work is a developpement of new synthetic route starting from different natural α -amino acids and to use obtained β,γ-diaminoacids to access novel unnatural peptides having specific conformational properties.The synthetic strategy, developed and optimized in our laboratory during this work, gives access to diastereomers cis and trans from L-leucine, L- and D-phenylalanine which were used in the synthesis of a new hybrid α/γ-peptides. The structural studies were performed on two series of hybrid α/γ-peptides consisting of β,γ-aminoacid from L-leucine and L- or D-α-amino acids. In the first case, the peptides are able to adopt stable secondary structures stabilized by intramolecular hydrogen bonds involving the nitrogen on the β-position. In addition, we present the synthesis of an analogue of gramicidine S, a naturally occuring antibiotic cyclic peptide. The dipeptide pattern D-Phe-L-Pro has been replaced with the β,γ-diaminoacid synthesized from D-phenylalanine
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Bouillère, Francelin. "Synthèse stéréosélective d'acides β,γ-diaminés : applications à l'étude structurale de nouveaux peptides". Paris 11, 2010. http://www.theses.fr/2010PA112359.
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L'étude d'oligomères non naturels qui adoptent des conformations similaires à celles des structures secondaires des protéines est un domaine en plein essor. Ces oligomères capables d'adopter une conformation spécifique, plus connus sous le nom de foldamères, sont des cibles intéressantes susceptibles de présenter des activités antibiotiques et peptidomimétiques. L'objectif de cette thèse est à la fois de permettre le développement d'une nouvelle voie de synthèse d'acides β,γ-diaminés énantiomériquement purs et de les utiliser pour accéder à de nouveaux peptides possédant des propriétés conformationnelles spécifiquesInterest in unnatural oligomers with strong conformational propensities (« foldamers ») akin to those of proteins has led to numerous recent explorations in this field. These oligomers are interesting targets as they can be valuable for specific applications such as protein-protein interactions or antibodies activity. The aim of this work is both to allow the development of a new synthetic route to enantiopure β,γ-diaminoacids and to use them to access to novel peptides having specific conformational properties
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Migliore, Mattia. "Recherche par modélisaion moléculaire de signatures RMN et DC caractéristiques pour les coudes β et y dans les peptides bioactifs. Characterization of β-turns by electronic circular dichroism spectroscopy : a coupled molecular dynamics and time-dependent density functional theory computational study". Thesis, Normandie, 2020. http://www.theses.fr/2020NORMR001.
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Ce travail de thèse a porté sur la recherche, par modélisation moléculaire, de signatures RMN et DC caractéristiques pour les coudes γ et β dans les peptides bioactifs. Les coudes γ et β, avec les hélices, constituent des motifs privilégiés de reconnaissance des peptides bioactifs par leurs cibles. Or, bien qu’il existe, au sein des structures de polypeptides, plusieurs catégories de coudes possédant des géométries différentes (2 types de coudes γ et 12 types de coudes β), peu d’outils expérimentaux sont disponibles pour aider à leur distinction. Ainsi, seuls 4 types de coudes β (I, I’, II et II’) ont, pour l’instant été caractérisés par RMN et il n’existe pas de spectre DC de référence fiable pour aucun motif de type coude. Dans un premier temps, afin d’élargir la base de données de RMN pour tous les types de coudes β (I, I’, II, II’, IV₁, IV₂, IV₃, IV₄, Via1, Via2, VIb et VIII) et γ (classique et inverse), nous avons analysé les paramètres structuraux caractéristiques de RMN (distances inter-hydrogènes et constantes de couplages ᶾJʜɴ-ʜꭤ) sur un ensemble de peptides modèles, extraits de la banque de protéines PDB et représentatifs de ces coudes. Les analyses des distances inter-hydrogènes ont permis d’identifier des signatures RMN caractéristiques pour différencier les deux types de coudes γ et certains types de coudes β (IV₁, IV₂,, VIb et VIII). La constante de couplage ᶾJʜɴ-ʜꭤ pourra servir à confirmer l’identification et à lever des ambiguïtés. Dans un second temps, en couplant dynamique moléculaire et TDDFT, nous avons simulé les spectres de DC de référence de peptides modèles adoptant des conformations de coudes β de type I, I’, II et II’. Les simulations ont permis de discerner deux familles de spectres DC caractéristiques : les types I/II’ d’un côté et les types I’/II de l’autre. L’ensemble de ces résultats indique que les coudes ne présentent pas nécessairement les mêmes signatures pour les deux techniques. La combinaison des signatures discriminantes de RMN et de DC pourrait donc permettre une meilleure identification des natures et des différents types de coudesThe aim of this work is to identify NMR and CD characteristic patterns for β- and γ-turns in bioactive peptides by molecular modelling. With helices, β- and γ-turns constitute favoured recognition motifs in bioactive peptides by their targets. Even though several classes of turns with different geometries exist in polypeptide structures (2 γ-turn types and 12 β-turn types), few experimental tools are available for their characterization. Thus, only 4 types of β-turns (I, I’, II et II’) have been, at present, described by NMR and there are no reliable reference CD spectra for turns. In order to extend the NMR data for all β- and γ-turn types, we analyzed NMR structural parameters (inter-hydrogen distances and ᶾJʜɴ-ʜꭤ coupling constants) in a representative peptide model dataset extracted from the PDB. The inter-hydrogen distance analysis allowed to identify specific NMR patterns for the two γ-turn types and for four β-turn types (IV₁, IV₂,, VIb and VIII). ᶾJʜɴ-ʜꭤ coupling constant may be used to confirm the identification and to remove ambiguities. Then, we simulated the reference CD spectra of model peptides adopting type I, I’, II and II’ β-turn conformations by combining molecular dynamic simulations and TDDFT computations. These computations allowed to determine two families of specific CD spectra : types I/II’, on one side and types I’/II, on the other. All these results indicate that the turns do not present the same patterns in both techniques. The combination of NMR and CD could therefore allow a better identification of the nature and the different types of turns
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Itkin, Anna. "Multidisniplinary study of Alzheimer's disease-related peptides : from amyloid precursor protein (APP) to amyloid β-oligomers and γ-secretase modulators". Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAF051/document.
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Une des caractéristiques histopathologiques de la maladie d'Alzheimer (AD) est la présence de plaques amyloïdes formées par les peptides amyloïdes β (Aβ) de 40 et 42 résidus, qui sont les produits de clivage par des protéases de l'APP. Afin de comprendre le rôle des variations structurelles du TM dans le traitement de l'APP, les peptides APP_TM4K ont été étudiés dans la bicouche lipidique en utilisant l’ATR-FTIR et ssNMR. Tandis que la structure secondaire globale du peptide APP_TM4K est hélicoidale, hétérogénéité de conformation et d'orientation a été observée pour le site de clivage γ et , que peuvent avoir des implications dans le mécanisme de clivage et donc dans la production d’Aβ. Les peptides Aβ s'agrègent pour produire des fibrilles et aussi de manière transitoire d'oligomères neurotoxiques. Nous avons constaté qu'en présence de Ca2+, l’Aβ (1-40) forme de préférence des oligomères, tandis qu'en absence de Ca2+ l'Aβ (1-40) s’agrège sous forme de fibrilles. Dans les échantillons sans Ca2+, l’ATR-FTIR révèle la conversion des oligomères en feuillets β antiparallèles en la conformation caractéristique des fibrilles en feuillets β parallèles. Ces résultats nous ont amené à conclure que les Ca2+ stimulent la formation d'oligomères d'Aβ (1-40), qui sont impliqués dans l’AD. Les positions et une orientation précise de deux nouveaux médicaments puissants modulateurs de la γ-sécrétase - le benzyl-carprofen et le sulfonyl-carprofen dans la bicouche lipidique, ont été obtenus à partir des expériences des ssNMR. Ces résultats indiquent que le mécanisme probable de modulation du clivage par la y-sécrétase est une interaction directe avec le domaine TM de l’APPA histopathological characteristic of Alzheimer’s disease (AD) is the presence of amyloid plaques formed by amyloid β(A) peptides of 40 and 42 residues-long, which are the cleavage products of APP by proteases. To understand the role of structural changes in the TM domain of APP, APP_TM4K peptides were studied in the lipid bilayer using ATR-FTIR and ssNMR. While the overall secondary structure of the APP_TM4K peptide is helical, conformational and orientational heterogeneity was observed for the y- and for the -cleavage sites, which may have implications for the cleavage mechanism and therefore the production of Aβ. Starting from its monomeric form, Aβ peptides aggregate into fibrils and / or oligomers, the latter being the most neurotoxic. We found that in the presence of Ca2 +, Aβ (1-40) preferably forms oligomers, whereas in the absence of a2 + Aβ (1-40) aggregates into fibrils. In samples without Ca2 +, ATR-FTIR shows conversion from antiparallel β sheet conformation of oligomers into parallel β sheets, characteristic of fibrils. These results led us to conclude that Ca2 +stimulates the formation of oligomers of Aβ (1-40), that have been implicated in the pathogenesis of AD. Position and precise orientation of two new drugs powerful modulators of γ-secretase benzyl-carprofen and carprofen sulfonyl in the lipid bilayer were obtained from neutron scattering and ssNMR experiments. These results indicate that carprofen-derivatives can directly interact with APP. Such interaction would interfere with proper APP-dimer formation, which is necessary for the sequential cleavage by β -secretase, diminishing or greatly reducing Aβ42 production
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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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Claudel, Stéphanie. "Les peptides Vinylogues : des nouveaux outils pour la préparation d'analogues contraints de la substance P, de γ-aminoacides α, β-hydroxylés et de dihydroxylactames". Nancy 1, 2004. http://www.theses.fr/2004NAN10039.
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Le travail présenté concerne la conception et la synthèse de peptides modifiés et se divise en deux parties. La première est l'introduction d'un résidu aminé vinylogue à stéréochimie cis et trans dans un undécapeptide, la substance P pour comprendre ses interactions avec le récepteur NK-1. Une seconde étude a été orientée vers l'obtention de g-aminopeptides par hydrogénation des acides aminés vinylogues précédents. Cette modification structurale a donné un nouvel analogue de la SP. La seconde partie est de la méthodologie de synthèse en utilisant les peptides vinylogues. Un premier chapitre, la dihydroxylation de ces motifs avec une induction asymétrique en utilisant des réactifs chiraux, permet l'obtention de g-aminoacides dihydroxylés. Un second chapitre, une application par la synthèse totale d'un produit naturel issu d'une plante nyctinastique. Et le dernier chapitre est une autre application, la synthèse de lactames dihydroxylés conduisant à la synthèse de nouveaux azasucresThis work concerns conception and synthesis of modified peptides and is divided in two parts. Firstly, it's the insertion of vinylogous amino acids with cis and trans conformation in neuropeptide of eleven amino acids which is substance P in order to understand its interaction with NK-1 receptor. A second study has been oriented on the preparation of g-amino peptides by hydrogenation of previous vinylogous amino acids. This structural modification has given a new SP's analog which has been tested. The second part is the methodology of synthesis using vinylogous peptides and is divided in three chapters. First one presents dihydroxylation's results of these residues with an asymmetric induction using chiral catalyst to obtain dihydroxylated g-amino acids. Second one is an application of these studies with a total synthesis of natural product extracted from nyctinastic plant. And the last one deals with preparation of dihydroxylated lactams leading to the synthesis of new azasugars
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Mazzier, Daniela. "Functionalized short peptides and polypeptides: from organic reactions, through secondary structure control, to supramolecular applications". Doctoral thesis, Università degli studi di Padova, 2016. http://hdl.handle.net/11577/3424844.
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Short helical peptides
Peptides with a well-defined helical conformation were examined with the aims of reinforcing their secondary structure or using their rigid conformation to control asymmetric induction over long distances.
In the first example, two consecutive i, i+4 intramolecular side chain-to-side chain macrocyclization reactions of different type, carried out on a preformed, partially helical linear peptide resulted in a double stapled, overlapping, bicyclic oligopeptide system. A detailed CD and NMR conformational study revealed that the mixed 310/α-helical conformation exhibited by the original linear peptide is converted into a fully-developed α-helix in the bicyclic peptide. In parallel, both the helix overall content and stability are significantly increased. In the second part, an achiral Aib-based helical foldamer was appropriately functionalized with the photoswitchable fumaramide/maleamide linkage, thus obtaining a system in which a screw sense preference may be activated by the absorption of UV light. The trans configuration in the fumaramide linkage holds the chiral residue away from the achiral portion of the oligomer, preventing the induction of a conformational preference. However, after photoisomerization, the cis configuration of the maleamide brings the chiral and achiral portions into proximity, generating a pronounced preference for one of the two possible, helical screw senses. In conclusion, we showed that it is feasible to use light to switch on and off the ability of the molecules to react strereoselectively in a chain extension reaction, or to modulate helix-to-helix communication.
Functionalized helical polypeptides
The well-known, rod-like α-helical polypeptide poly(γ-benzyl-L-glutamate) (PBLG) was selected for this study. The possibility to create self-assembled microstructures with different characteristics, shapes and functions from different PBLG-conjugates was explored.
Mono- and bis-fullerene (C60)-PBLG conjugates were obtained by one-pot thiol-ene chemistry. These systems showed the propensity to self-assemble in water creating precise bulky microstructures of toroidal or vesicular shape. In a second part, we reported the synthesis of star-shaped carbon quantum dots (CQDs)-PBLG conjugates that self-assemble into microstructures and retain the characteristic emission properties of the native dots. CQDs, prepared by microwave-assisted carbonization of Arg and 1,2-ethylendiamine in water, were used either as initiators to afford a daisy-like peptide-polymer structure, or as capping agents towards more elaborated hybrid nanostructures that self-assemble into supramolecular aggregates of spherical shape. Finally, smart microstructures with photoresponsive behavior was obtained by the insertion of azobenzene-containing α-amino acids in PBLG systems. We created two systems, with either C2- or C3-symmetry, that self-assemble in spherical structures. The change in their 3D-structure after light irradiation is followed by a variation in the morphology of the aggregates.
Self-assembling short peptides
The synthesis and self-assembly properties of two different peptide systems were studied. The first series of compounds contain the photoswitchable α-amino acid bis[p-(phenylazo)benzyl]glycine, which undergoes a reversible cis-trans isomerization upon exposure to light at the appropriate wavelengths. Derivatives and short peptides containing this α-amino acid are able to promote the formation of well-ordered supramolecular structures. Interestingly, the morphological transition observed after UV-light irradiation proved to be reversible due to the presence of the two side-chain azobenzene groups.
In the second part, we investigated the hydrophobic, terminally-protected dipeptide Boc-L-Cys(Me)-L-Leu-OMe that it is able to hierarchically self-assemble producing nano-, micro- and macroscale complex architectures, including hollow rods, under appropriate conditions. Our results suggested that its self-assembly properties might be related to the occurrence in its single crystal structure of a supramolecular sixfold helix motif. Subsequently, we decided to chemically modify the molecule to obtain a diacetylene derivative. This final compound is able to form an organogel or spherical aggregates, which undergo a topochemical polymerization under UV-light irradiation.Peptidi elicoidali corti In questo lavoro di tesi sono stati studiati diversi peptidi caratterizzati da una ben definita conformazione elicoidale con lo scopo di stabilizzarne la struttura secondaria oppure di sfruttare la loro conformazione rigida come mezzo per controllare l’induzione asimmetrica su lunghe distanze. Il primo esempio, un sistema oligopeptidico biciclico doppiamente stabilizzato, è stato ottenuto tramite due reazioni di macrociclizzazione che hanno coinvolto le catene laterali dei residui in posizione i e i+4 di un peptide lineare. Un’indagine conformazionale dettagliata, condotta utilizzando le spettroscopie CD ed NMR, ha rivelato che la conformazione mista 310/α-elica, osservata per il peptide lineare, risulta completamente convertita in una struttura ad elevato contributo α-elicoidale nel peptide biciclico. In parallelo, sia il contenuto totale di elica sia la stabilità risultano significativamente aumentati. Nel secondo caso, un foldamero achirale elicoidale a base di Aib è stato opportunamente funzionalizzato con il gruppo fotoisomerizzabile fumarammide/maleammide contenente un residuo chirale. In questo modo è stato ottenuto un sistema in cui è stato possibile influenzare il senso di spiralizzazione dell’elica grazie all’uso di luce ultravioletta. La configurazione trans nella fumarammide, infatti mantiene il residuo chirale lontano dal segmento achirale dell’oligomero, rendendo impossibile l’induzione di una conformazione preferenziale. Tuttavia dopo l’isomerizzazione, la configurazione cis della maleammide consente alla parte chirale e a quella achirale di essere spazialmente vicine, con conseguente induzione di chiralità e adozione di un senso preferenziale di spiralizzazione. Sfruttando questo principio è stato quindi possibile utilizzare la luce per accendere o spegnere la capacità del sistema di reagire stereoselettivamente, oppure di modulare la comunicazione di chiralità tra due segmenti elicoidali. Polipeptidi elicoidali funzionalizzati Con lo scopo di ottenere tramite self-assembly microstrutture con differenti caratteristiche, forme e funzioni sono stati sintetizzati diversi sistemi coniugati a base di poli(γ-benzil-L-glutammato) (PBLG). Sistemi polipeptidici contenenti una o due unità di fullerene sono stati ottenuti tramite reazione tiol-ene one-pot. Questi due polimeri hanno mostrato una diversa propensione ad auto-assemblarsi in ambiente acquoso, formando microstrutture di forma toroidale oppure di tipo vescicolare. Come ulteriore esempio è stata riportata la sintesi di sistemi coniugati a base di PBLG e carbon quantum dots. I CQDs, preparati per trattamento in microonde a partire da una soluzione acquosa di arginina e 1,2-etilendiammina, sono stati usati come iniziatore, ottenendo una struttura polimerica a forma di stella, oppure come agente cappante, portando alla formazione di microstrutture più complesse. I sistemi ottenuti sono in grado di autoassemblarsi formando aggregati supramolecolari di forma sferica che mantengono le caratteristiche proprietà di emissione dei dots originali. Infine, microstrutture “smart” con comportamento fotoresponsivo sono state ottenute inserendo amminoacidi a base di azobenzene all’interno del sistema polipeptidico. Sono state quindi sintetizzate due strutture polipeptidiche con simmetria C2 e C3 che hanno evidenziato la formazione di strutture sferiche tramite self-assembly. Il cambiamento della loro struttura tridimensionale in seguito ad irraggiamento è accompagnato da una variazione nella morfologia degli aggregati. Peptidi corti auto-assemblanti In questo ultimo capitolo sono discusse la sintesi e le peculiari proprietà di self-assembly mostrate da due diversi sistemi peptidici. La prima serie di composti contiene l’amminoacido fotoisomerizzabile bis[p-(fenilazo)benzil]glicina, che è in grado di isomerizzare reversibilmente tra le due forme cis/trans in seguito ad irraggiamento con luce di adeguata lunghezza d’onda. Derivati e peptidi corti contenenti questo amminoacido sono in grado di promuovere la formazione di strutture supramolecolari ordinate. Inoltre, grazie alla presenza delle due unità di azobenzene sulle catene lineari, la transizione morfologica osservata in seguito ad irraggiamento si è dimostrata essere reversibile. Nella seconda parte di questo studio è stato esaminato il comportamento del dipeptide idrofobico protetto Boc-L-Cys(Me)-L-Leu-OMe. La formazione di nano-, micro- e macro- architetture complesse, tra cui bacchette caratterizzate da una cavità interna, è stata osservata in diverse condizioni sperimentali. I risultati ottenuti suggeriscono che le proprietà di self-assembly sono correlate all’organizzazione delle molecole nel cristallo singolo in cui è stata osservata la presenza di una particolare struttura supramolecolare elicoidale formata da sei molecole. Successivamente è stato deciso di modificare il dipeptide in modo da ottenere un derivato diacetilenico. Questo derivato è in grado di formare un organogel o delle strutture sferiche che possono subire polimerizzazione topochimica per irraggiamento UV.
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Romero, Eugénie. "Synthèse et étude conformationnelle d’α-hydrazinopeptides linéaires et cycliques". Thesis, Université de Lorraine, 2015. http://www.theses.fr/2015LORR0232/document.
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La formation de nanostructures bien définies par autoassemblage de briques organiques a reçu de nombreuses attentions dues à leurs potentielles applications en chimie comme en biologie. Parmi toutes ces éléments organiques, les peptides et pseudopeptides font partie des plus prometteurs de par leur ressemblance aux protéines. Nous pouvons dénombrer de nombreux autoassemblages peptidiques, comme les nanotubes, les nanofibres, les vésicules, les nanosphères etc… Dans ce contexte, nous nous sommes intéressés à la synthèse et à l’étude structurale globale des hydrazinopeptides. Grâce à leur azote supplémentaire, ces pseudopeptides bis-azotés sont capables de s’auto-assembler en de nouvelles structurations. Les 1:1[α/α-Nα-Bn-hydrazino]peptides linéaires ont démontré se structurer en hydrazinoturn et γ-turn en solution. Nous mettrons en évidence la capacité des analogues 1:1[ß/α-Nα-Bn-hydrazino]peptides linéaires à s’autostructurer en hydrazinoturn en solution, n’impliquant pas le squelette du motif ß-aminoacide. De la même manière, nous démontrerons la capacité des pseudopeptides purs hydrazino à se structurer en solution en une structure très solide formées de successions d’hydrazinoturn, observable à l’état cristallin également. Dans un deuxième temps, et dans le cadre de l’élaboration de structures nanotubulaires, nous avons étudié une série de 1:1[α/α-Nα-Bn-hydrazino]peptides cycliques, et tout particulièrement les cyclotétramères. Dans ce contexte, nous avons cherché à mettre en lumière les différents paramètres pouvant influencer l’organisation nanotubulaires dans nos macrocycles, dans le but d’élaborer la meilleure stratégie afin d’obtenir cette nanostructuration en vues d’éventuelles applications. Les différents paramètres étudiés sont les suivants : la stratégie de synthèse, la chiralité, l’orientation des chaînes latérales, et enfin l’aptitude à former des gelsThe formation of nanostructures with well-defined organic brick self-assembly has received much attention due to their potential applications in chemistry and biology. Among all these organic elements, peptides and pseudopeptides are among the most promising because of their similarity to proteins. We can enumerate many peptides self-assembly, such as nanotubes, nonafibres, vesicles, nanospheres etc … In this context, we are interested by the synthesis and overall structural study of hydrazinopeptides. Thanks to the additional nitrogen, these bis-nitrogen pseudopeptides are able to self-assemble into new structuring. The 1:1[α/α-Nα-Bn-hydrazino] linear peptides showed coalesce into hydrazinoturn and γ-turn in solution. We have highlighted the ability of analogues of 1:1[ß/α-Nα-Bn-hydrazino] linear peptides to be structured in hydrazinoturn only, in solution. Similarly, we have demonstrated the ability of pure α-Nα-Bn-hydrazino pseudopeptides to be structured in a very solid solution structure formed of hydrazinoturn observable also in crystal state. Secondly, and as part of the development of nanotube structures, we have studied a serie of 1:1[α/α-Nα-hydrazino] cyclic peptides, and especially cyclotetrameres. In this context, we have sought to highlight the various parameters that may affect the organization in nanotubes, in order to develop the best strategy to achieve this potential application in nanostructuring views. The various parameters studied are: the synthetic strategy, the chirality, the orientation of side chains, and finally the ability to form gels
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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
Części książek na temat "Γ-peptides"
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Pavone, V., A. Lombardi, G. D’Auria, M. Saviano, B. Blasio, L. Paolillo i C. Pedone. "Molecular tools for the design of γ-turn in peptides". W Peptides, 366–67. Dordrecht: Springer Netherlands, 1992. http://dx.doi.org/10.1007/978-94-011-2264-1_135.
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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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Colpitts, T., i F. J. Castellino. "Ca2+ Binding properties of synthetic γ-carboxyglutamic acid containing peptides homologous to protein C". W Peptides, 932–33. Dordrecht: Springer Netherlands, 1994. http://dx.doi.org/10.1007/978-94-011-0683-2_312.
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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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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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Guichard, Gilles. "β-Peptides, γ-Peptides and Isosteric Backbones: New Scaffolds with Controlled Shapes for Mimicking Protein Secondary Structure Elements". W Pseudo-Peptides in Drug Development, 33–120. Weinheim, FRG: Wiley-VCH Verlag GmbH & Co. KGaA, 2005. http://dx.doi.org/10.1002/3527601902.ch2.
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Seebach, Dieter. "Homologs of Amino Acids and Explorations into the Worlds of β- and γ-Peptides". W Peptides: The Wave of the Future, 569–71. Dordrecht: Springer Netherlands, 2001. http://dx.doi.org/10.1007/978-94-010-0464-0_264.
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Rueping, Magnus, Bernhard Jaun i Dieter Seebach. "Folding of β- and γ-Peptides — the Influence of Substitution Patterns on the Formation of Secondary Structures". W Peptides: The Wave of the Future, 383–84. Dordrecht: Springer Netherlands, 2001. http://dx.doi.org/10.1007/978-94-010-0464-0_177.
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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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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.
Pełny tekst źródłaStreszczenia konferencji na temat "Γ-peptides"
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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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Yoshida, N., S. Terukina, M. Matsuda, M. Moroi, M. Okuma i N. Aoki. "FIBRINOGENS KYOTO AND TOCHIGI, EACH WITH AN APPARENT ABNORMAL MOL. WT. γ CHAIN, ARE CHARACTERIZED BY REPLACEMENT OF γ ASN-308 BY LYS AND γ ARG-275 BY CYS, RESPECTIVELY". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644702.
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Congenital inherited abnormal fibrinogens (Fbgs) Kyoto and Tochigi showed prolonged thrombin- and reptilase-time, normal release of fibrinopeptides A and B, normal cross linking ability and impaired polymerization of the fibrin monomer.Purified Fbg analyzed on SDS-PAGE under the reduced condition in the system of Laemmli contained 50 % of an apparent lower mol. wt. γ chain (γ Kyoto)(mol. wt.= 48,000 compared with 50,000 for the normal) in Fbg Kyoto and an apparent higher mol. wt. γ chain (γ Tochigi)(mol. wt.= 50,500) in Fbg Tochigi. Apparent mol. wt. differences were also detected in reduced and carboxymethyl ated Fbg, Fbg fragment D1, and D2, but not in D3. This suggested that the abnormality of γ chains in both Fbgs is in γ 303-356.Amino acid sequence analysis was performed for CNBr- or lysylendopeptidase-digested peptides of the γ chain or D1 peptides after fractionation on HPLC. In Fbg Kyoto, γ Asn-308 was substituted by Lys, and a deletion of short peptides corresponding to the mol. wt. difference of 2,000 could not be detected. In Fbg Tochigi, γ Arg-275 was substituted by Cys, and no abnormality of amino acid sequence was found in γ 303-356.These results suggest that some lesions or conformations containing γ 275 and γ 308 will directly or indirectly affect polymerization of fibrin monomers. Although the reason for apparent mol. wt. differences is not known yet, SDS-PAGE in the system of Laemmli will be useful for the analysis of abnormal Fbgs.Fbg Kyoto could not be separated into two or three populations and may contain hetero-dimer molecules, but Fbg Tochigi had unclottable Fbg with predominant γ Tochigi and may contain abnormal homo-dimer molecules and normal molecules.
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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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Guha, Snigdha. "Efficacy of Great Northern Beans-derived γ-glutamyl Peptides in Reducing Vascular Inflammation". W 2022 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2022. http://dx.doi.org/10.21748/pykq1684.
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The prevalence of cardiovascular diseases (CVDs) is estimated at nearly 37% in the United States. Elevated blood glucose, elevated triglycerides, high blood pressure, and low levels of high-density lipoprotein, result in increased levels of inflammation and pathogenesis of various CVDs such as atherosclerosis and hypertension. Dietary γ-glutamyl peptides (γ-GPs), naturally found in dry beans, have exhibited beneficial biological activities to reduce chronic inflammation. One such type of dry bean, Great Northern bean (GNB), is an important agricultural commodity for the US and for the state of Nebraska. The present study developed a green-chemistry-based scalable technology for isolating the γ-GPs from GNBs. The γ-GPs-enriched fraction can significantly reduce vascular inflammation in human endothelial cells. The γ-GP (γ-EV) found in various foods including beans, can significantly reduce the tumor necrosis factor-ɑ (TNF-ɑ)-induced increased expression of inflammatory adhesion molecules (VCAM-1, E-Selectin), chemokine (MCP-1), and cytokines (IL-6 and IL-8) in human aortic endothelial cells. The anti-inflammatory effect of γ-EV is mediated through the allosteric activation of calcium-sensing receptor (CaSR). The route of transport of γ-EV across the intestinal monolayer was found to be via the PepT1 and paracellular pathways with the apparent permeability (Papp) of 1.56×10–6cm/s. Furthermore, γ-EV was found to be effective in reducing vascular inflammation in vivo, in a high-fat diet (HFD: 40 kcal% fat, 1.25% cholesterol) feed ApoE-/- mice, where γ-EV intervention (150mg/kg BW) significantly reduced the expression of inflammatory biomarkers such as VCAM-1, ICAM-1, LOX-1, and improved the pathological characteristics of the atherosclerotic plaques in the aorta. In addition, the splenic FoxP3+ and CD25+ cells within the total lymphocyte population were significantly decreased in the γ-EV-treated group. Thus, the present study highlights the potential use of γ-glutamyl peptides, as a functional food ingredient for the prevention and management of CVDs.*Snigdha Guha, Honored Student Award Winner; Peter and Clare Kalustian Award Winner*
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Andrieux, A., M. H. Charon, G. Hudry-Clergeon i G. Marguerie. "FIBRINOGEN SEQUENCES INTERACTING WITH PLATELET GPIIbIIIa". W XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643519.
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Fibrinogen (Fg), fibronectin (Fn) and von Willebrand factor (vWF), interact with GPIIbllla on AD? stimulated platelets, and a common mechanism has been postulated for the binding of these adhesive proteins. Fg, Fn and vWF contain the tripeptide Arg-Gly-Asp and synthetic analogues to this sequence inhibit their interaction with platelet and their concomitant adhesive reactions. On the other hand, sequences corresponding to the Fg γ chain inhibit the binding of Fg, Fn and vWF to platelet and may also represent a potential recognition site. This raises the possibility that the γ chain sequence and Arg-Gly-Asp interact with the same site or represent primary and secondary sites for the Fg molecule. Within this context, the capacity of these sequences to interact with GPIIbllla and to block fibrinogen binding were compared. The smallest γ chain sequence that was active in inhibiting this reaction was the hexamer Lys-Gln-Ala-Gly-Asp-Val corresponding to the last six amino acid residues at the C-terminus of the γ chain. In parallel, peptides with the structure Arg-Gly-Asp-X were synthesized and tested in vitro. The activity of these peptides was dependent upon the hydrophobicity of the amino acid residue at position X. Arg-GLy-Asp-Phe corresponding to the sequence at position 95-98 in the Fg Aα chain was 5 to 10 times more active than Arg-GLy-Asp-Ser, present at position 572-575 in the Aα chain, and was 10 to 20 times more active than the γ chain hexamer. Both the Aα chain and γ chain sequences however, inhibited Fg binding by greater than 90%. When the γ chain sequence and the Arg-Gly-Asp-X sequence were coupled to Sepharose, GPIIbIIIa interacted with these sequences and was eluted from each column by either of the peptides. Finally direct binding experiments indicated that Arg-Gly-Asp-X and γ chain sequences are competitive antagonists. These results suggest that both sequences interact with the same site on GPIIbIIIa and comparison of the hydrophilicity of these peptides suggests that the binding domain on GPIIbIIIa exhibits hydrophobic properties.
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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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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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Guha, Snigdha, i Kaustav Majumder. "Efficacy of Great Northern Beans-derived γ-glutamyl Peptides in Reducing Vascular Inflammation". W Virtual 2021 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2021. http://dx.doi.org/10.21748/am21.308.
Pełny tekst źródłaRaporty organizacyjne na temat "Γ-peptides"
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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.