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Synthesis and self assembling properties of click triazole-based peptidomimetics. / CUHK electronic theses & dissertations collectionJanuary 2012 (has links)
本論文報道了 (a) 基於1,4-二取代 1,2,3-三唑的短肽類似物的合成及表徵,和 (b)這些類肽化合物在溶液相中的自組裝及凝膠化特性研究。 / 本論文第一章簡單地介紹及槪括基於三唑的寡聚物的構象和超分子的屬性。 / 本論文第二章報告1,4-二取代 1,2,3-三唑在類肽化合物中作為聯繫單元和作為構象控制的多功能性。 / 本論文第三章敍述了一類新的包含1,2,3-三唑在分子骨幹中的類肽化合物的合成及表徵。以炔丙胺/炔丁胺和 α-疊氮酸作為雙官能團前體,不同氨基酸成分和不同C-端基的系列類肽化合物由反覆的合成過程製備而來。用炔丙醇代替炔丙胺, 相應的酯類似物也被製備用作比較研究。 / 本論文第四章敍述了這些類肽化合物的自組裝及凝膠化特性。根據一維¹H 核磁共振,二維核磁共振 (2D),氫/氘交換核磁共振 (H/D), 蒸汽壓力均分子量 (VPO), 圓二色譜 (CD) 和紅外光譜分析研究,基於三唑類的短肽化合物Boc-aa¹aa²***aa[superscript n]-X 被發現以頭接尾的方式自我二聚 (K[subscript dsubscript isubscript m] ~10-680 M⁻¹)。二聚常數 (K[subscript dsubscript isubscript m])隨著氨基酸單位數目的增加而增大。在相同的寡聚系列中,K[subscript dsubscript isubscript m]值受到C-端基的大小的強烈影響。三肽類似物Boc-aa¹aa²aa³-X 還是許多芳烴類溶劑的優秀有機凝膠因子。掃描電子顯微技術(SEM)形態研究顯示三維網路形成於凝膠過程中。另一方面,結果顯示,類肽化合物的連結器長度在二級結構的形成和自組裝特性上發揮重要作用。 / 爲了進一步發展頭尾二聚的概念,本論文第五章敍述頭接尾的β-髮夾類似結構可通過適當的連結器偶聯兩個基於三唑的三肽類似物來獲得,如4-羥基脯氨酸的衍生物。一維¹H 核磁共振,二維核磁共振 (2D),氫/氘交換核磁共振 (H/D)和紅外光譜等分析方法被用來研究其自組裝特性。 / 這篇論文展示了用三唑類體系結構設計類肽分子的可行性。產品結構表徵及性質探索的結果為這些新的類肽化合物的進一步調查和應用奠定了基礎。 / This thesis reported (a) the synthesis and characterization of 1,4-disubstituted 1,2,3-triazole-based oligopeptides, and (b) the study on self assembling and gelation properties of the peptidomimetic compounds. / Chapter one gave a brief introduction and review on the click triazole-based oligomers, including their conformational and supramolecular properties. / Chapter two reviewed the versatility of 1,4-disubstituted 1,2,3-triazole unit as a linker and as a conformational controlling unit in peptidomimetics. / Chapter three disclosed the synthesis and characterization of a new class of linear peptidomimetics incorporating 1,2,3-triazoles in the backbone. Several series of click peptidomimetics, containing up to four amino acid residues and of different amino acid compositions and different C-terminal groups, were prepared by an iterative synthetic procedure, in which propargyl amine/homopropargyl amine and α-azido acids were used as bifunctional precursors. Using propargyl alcohol instead of propargyl amine, the corresponding ester analogs were also prepared for comparison studies. / In chapter four, the self-assembly and gelation properties of these peptidomimetics were illustrated. Click triazole-based oligopeptides Boc-aa¹aa²***aa[superscript n]-X (n = 2, 3 or 4) were found to self-dimerize (K[subscript dsubscript isubscript m] ~ 10-1020 M⁻¹) in a head-to-tail fashion according to ¹H NMR, two-dimensional NMR (2D), hydrogen/deuterium (H/D) exchange NMR, vapor pressure osmometry (VPO), circular dichroism (CD) and FT-IR studies. The dimerization constant (K[subscript dsubscript isubscript m]) was found to increase with increasing number of the amino acid units. Within the same oligomeric series, the K[subscript dsubscript isubscript m] value was strongly affected by the size of the C-terminal end group. The tripeptides Boc-aa¹aa²aa³-X were also excellent organogelators of many aromatic solvents. Morphological study indicated thata three-dimensional network was formed during the gelation process. On the other hand, the corresponding triester analog 98 and elongated analogs l-Boc-aa¹aa²aa³-Prg did not exhibit any self assembling properties. This revealed that the linker length and the amide units inside the click peptidomimetics played an important role in both the formation of secondary structures and the self-assembly properties. / To further develop the idea of head-to-tail dimerization, chapter five described the head-to-tail β-hairpin like structures could be obtained by conjugating two click triazole-based tripeptides through an appropriate linker such as derivatives of 4-hydroxyproline. Analytical methods, such as ¹H NMR, two-dimensional NMR, H/D exchange NMR spectroscopy, and FT-IR studies, were used to determine their self assembling properties. / This thesis has demonstrated the feasibility of designing peptidomimetic molecules with the triazole architecture. The results of the product characterization and property exploration have laid down the groundwork for further investigation and application of this new of peptidomimetic compounds. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Ke, Zhihai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 156-162). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Table of Contents --- p.i / Acknowledgements --- p.iv / Abbreviations --- p.v / Abstract --- p.vi / Publications related to this thesis --- p.x / Chapter Chapter One --- Click ChemistryA Powerful Tool to Create Supramolecular Chimeras / Chapter 1.1 --- Introduction to Click Chemistry --- p.1 / Chapter 1.2 --- General Synthetic Strategies of Acyclic Oligotriazoles --- p.6 / Chapter 1.3 --- Conformational Properties --- p.9 / Chapter 1.3.1 --- Helical Structures from Oligotriazoles --- p.9 / Chapter 1.3.2 --- Double Helical Structure from Oligotriazoles --- p.12 / Chapter 1.3.3 --- β-Strands and β-sheets derived from Oligotriazoles --- p.13 / Chapter 1.4 --- Supramolecular Properties --- p.14 / Chapter 1.4.1 --- Host-guest Binding --- p.14 / Chapter 1.4.2 --- Self Assembling Properties --- p.17 / Chapter 1.4.3 --- Chemosensing Properties --- p.19 / Chapter Chapter Two --- Click PeptidomimeticsTricks with Clicks / Chapter 2.1 --- Click ChemistryA New Ligation Tool for Peptidomimetics Synthesis --- p.20 / Chapter 2.2 --- Click Peptidomimetics --- p.22 / Chapter 2.2.1 --- Peptidepeptide --- p.23 / Chapter 2.2.2 --- Polymerpeptide --- p.25 / Chapter 2.2.3 --- Dendrimerpeptide --- p.26 / Chapter 2.2.4 --- Small moleculepeptide --- p.27 / Chapter 2.3 --- The triazole linkage as conformational control --- p.29 / Chapter 2.3.1 --- Triazole-based β-turn mimetics --- p.29 / Chapter 2.3.2 --- Cyclic turn mimetics --- p.31 / Chapter 2.3.3 --- Cis/trans-prolyl mimic --- p.33 / Chapter 2.3.4 --- Triazoles in helix bundles --- p.34 / Chapter 2.4 --- Oligotriazole peptides --- p.35 / Chapter 2.5 --- Summary and Aim of the Project --- p.36 / Chapter Chapter Three --- Design, Synthesis and Characterization of Oligotriazole-based Peptidomimetics / Chapter 3.1 --- Synthetic Design --- p.38 / Chapter 3.2 --- Choice of Reaction Conditions --- p.40 / Chapter 3.3 --- Synthesis of Linear Click Triazole-based Peptidomimetics --- p.41 / Chapter 3.3.1 --- Preparation of Click Triazole-based Peptidomimetics with Shorter Linkers --- p.42 / Chapter 3.3.2 --- Preparation of Click Triazole-based Peptidomimetics l-Boc-aa¹aa²**aa[superscript n]-X with a Longer Spacer --- p.47 / Chapter 3.3.3 --- Preparation of ester analogs and other model compounds --- p.49 / Chapter 3.4 --- Characterization of Linear Click Triazole-based Peptidomimetics --- p.51 / Chapter 3.4.1 --- Nuclear Magnetic Resonance (NMR) Spectroscopy --- p.52 / Chapter 3.4.1.1 --- ¹H NMR Spectroscopy --- p.52 / Chapter 3.4.1.2 --- ¹³C NMR Spectroscopy --- p.57 / Chapter 3.4.2 --- Mass Spectrometry Analysis --- p.59 / Chapter 3.4.3 --- High-performance Liquid Chromatography Analysis --- p.61 / Chapter 3.5 --- Conclusions --- p.62 / Chapter Chapter Four --- Self-Assembling Properties of Click Triazole-based Peptidomimetics / Chapter 4.1 --- Introduction --- p.63 / Chapter 4.2 --- Results and Discussion --- p.65 / Chapter 4.2.1 --- Nuclear Magnetic Resonance (NMR) Spectroscopy --- p.65 / Chapter 4.2.1.1 --- Variable Concentration ¹H NMR --- p.65 / Chapter 4.2.1.2 --- Two-dimensional ¹H NMR --- p.71 / Chapter 4.2.1.3 --- Hydrogen/deuterium (H/D) exchange --- p.74 / Chapter 4.2.2 --- Vapor Pressure Osmometry (VPO) --- p.77 / Chapter 4.2.3 --- Infra-red (IR) Spectroscopy --- p.78 / Chapter 4.2.4 --- Theoretical Calculation --- p.80 / Chapter 4.2.5 --- Circular Dichroism (CD) --- p.81 / Chapter 4.2.6 --- Gelation Behaviors --- p.83 / Chapter 4.2.6.1 --- General Gelation Properties --- p.83 / Chapter 4.2.6.2 --- Morphology Studies --- p.87 / Chapter 4.3 --- Conclusions --- p.90 / Chapter Chapter Five --- β-Hairpin Structure from Click Triazole-based Peptidomimetics / Chapter 5.1 --- Introduction and Design of β-hairpin --- p.91 / Chapter 5.2 --- β-Hairpin Like Click Triazole-based Peptidomimetics Based on a Bifunctional Aromatic Linker 105 --- p.92 / Chapter 5.3 --- β-Hairpin Like Click Peptidomimetics Based on a Proline Linker 113 --- p.97 / Chapter 5.4 --- Conclusions --- p.107 / Chapter Chapter Six --- Conclusion and Outlook --- p.109 / Chapter Chapter Seven --- Experimental Procedures / Chapter 7.1 --- General Information --- p.112 / Chapter 7.2 --- Experimental Procedures --- p.113 / Chapter 7.3 --- Other Experimental --- p.152 / References --- p.156 / Chapter Appendix 1 --- (Nuclear Magnetic Resonance Spectra) --- p.A1 / Appendix 2 --- p.A111
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Novel Methods for the Ribosomal Incorporation of β-Amino AcidsSanguineti, Gabriella January 2016 (has links)
Protein-protein interactions (PPIs) dominate all cellular functions across every domain of life. If PPIs become aberrant, they may result in many human diseases, such as cancer or Alzheimer’s. Despite their clinical significance, modulating aberrant PPIs is a daunting task. Most PPI surfaces are long, hydrophilic and structurally complex. Thus, finding molecules that moderate specific aberrant PPIs is an important goal in drug discovery research. For example, PPIs have been modulated by peptidomimetics, synthetic peptides that assume three-dimensional structures similar to proteins, but unlike natural peptides, they are proteolytically stable. However, building libraries of peptidomimetics is challenging as current methods rely on solid phase peptide synthesis, which limits the size and diversity of peptidomimetic libraries. As such, using the translation machinery to synthesize peptidomimetics is an attractive approach.
In Chapter 1, we begin by discussing bacterial protein synthesis. Then, we delve into a detailed discussion of the application of the bacterial translation machinery for the in vitro translation of synthetic peptides. In this discussion, we review the different technologies, their advantages and limitations with respect to the incorporation of amino acids with unnatural backbones.
After reviewing the methods used to incorporate backbone analogs, and their compatibility with the bacterial translation machinery, we describe a novel approach for the ribosomal incorporation of -amino acids analogs containing an -substituent, -hydroxy--amino acids (Chapter 2). We demonstrate that the ribosome incorporates this new class of substrates through the formation of an intermediate ester bond that rapidly rearranges to form a native peptide bond. Using this approach, we show that -hydroxy--amino acid single incorporation efficiencies are comparable the incorporation efficiencies obtained with natural amino acids.
In Chapter 3, we apply this approach to the synthesis of peptides containing multiple -hydroxy--amino acids. This chapter describes the results obtained with the in vitro synthesis of peptides containing two consecutive -hydroxy--amino acids, three consecutive -hydroxy--amino acids, and alternating -hydroxy--amino acids and -amino acids. Based on these results, we propose experiments to improve these incorporation yields for the application of this technology for the in vitro synthesis of diverse peptidomimetic libraries.
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Amphiphilic peptides containing alternating α-aminoxy acids and α-amino acids to mimic the α-helix of bak BH3 domain and disulfide bondas covalent linkage for stabilizing 7/8 helixZhang, Ting, 张婷 January 2011 (has links)
The binding between the survival protein Bcl-xL and the death-promoting region of
the Bcl-2-related protein Bak is one of the key protein-protein interactions in the
regulation of programmed cell death (apoptosis). Since it is well recognized that the
BH3 domain of Bak adopts an amphipathic α-helix to interact with Bcl-xL through
hydrophobic and electrostatic effects, conformational studies and possible
applications of the α-aminoxy acid-containing peptides as mimics of the α-helix of
Bak BH3 domain have been carried out. The main results are summarized below.
Four short peptides ZT1?ZT4 containing alternating α-aminoxy acids/α-amino acids
as the mimics of the α-helix of Bak protein were designed and synthesized. However,
none of these four peptides, at the concentration of 25 μM, exhibited a significant
inhibitory effect on the Bcl-xL inhibition test. Circular dichroism spectroscopic
studies on ZT1?ZT4 as well as short model peptides N-minus, N-plus, C-minus and
C-plus suggest that the proposed secondary structure, the 7/8 helix, is not stable in
aqueous solutions.
1H NMR, 2D NMR and circular dichroism spectroscopic studies on the disulfide
bond-constrained short peptides 4.7?4.9 with alternating α-aminoxy acids and
α-amino acids suggest that a disulfide linker with three methylene units between
adjacent α-amino acid residues could dramatically increase the stability of the 7/8
helix even in a mixed buffer/methanol solution.
1H NMR, 2D NMR and circular dichroism spectroscopic studies have also revealed
that the hybrid soluble peptides C-free, N-free and Both-free containing α-amino
acids and β-2,2-cyclopropyl-amino acids adopted a stable 8/8 helix in aqueous
solution. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy
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SYNTHESIS, BIOLOGICAL ACTIVITY AND CONFORMATIONAL ANALYSIS OF FRAGMENT ANALOGUES OF ALPHA-MELANOTROPIN (PEPTIDE, STRUCTURE-FUNCTION, PHENYLGLYCINE, NMR, TETRAHYDROISOQUINOLINE-3-CARBOXYLATE).CODY, WAYNE LIVINGSTON. January 1985 (has links)
α-MSH (α-melanotropin) is a naturally occurring linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂) that is primarily known for its ability to stimulate integumental melanocytes and more recently has been implicated in a variety of physiological and neurological processes. It has been shown that substitution of D-phenylalanine in the seven position of this hormone led to an analogue with increased potency and prolonged biological activity. Furthermore, cyclization between the four and ten positions via a cystine bridge led to analogues with enhanced potency. In this regard, a series of conformationally restricted linear and cyclic fragment analogues of α-MSH have been prepared and carefully analyzed by both biological and biophysical methods. Conformational restriction was incorporated in α-MSH fragment analogues, by: (1) substitution of sterically restricted amino acids into the native sequence; or (2) cyclization of the peptide via a disulfide bridge. Due to the biological differences observed for these synthetic α-MSH fragment analogues, a complete conformational analysis by both proton and carbon-13 NMR was performed. The conformational preferences of the backbone were examined by analyzing: (1) the alpha proton chemical shifts; (2) the amide proton chemical shifts; (3) the amide proton coupling constants; and (4) the amide proton temperature dependencies. The data suggests that the peptide backbone in both linear and cyclic analogues possesses a great amount of conformational flexibility with no hydrogen-bonded stabilization. The three-dimensional orientations of individual amino acid side chains have been examined by analyzing: (1) the chemical shifts of the side chain protons; (2) the alpha-beta coupling constants (corresponding rotamer populations); and (3) the carbon-13 spin lattice relaxation times (T₁). A careful examination a the chemical shifts of the side chains of individual amino acids in linear α-MSH fragments reveals that incorporation of an aromatic D-amino acid in the seven position results in an interaction of the side chains of the six, seven and eight positions. In addition, the low carbon-13 spin-lattice relaxation times for the β-carbons of the 5-9 sequence for both Ac-[Nle⁴]-α-MSH₄₋₁₁-NH₂ and Ac-[Nle⁴, D-Phe⁷]-α-MSH₄₋₁₁-NH₂, provides further evidence for an interaction of these side chains. Similar shielding patterns have been observed for the cyclic α-MSH fragment analogues depending upon whether L- or D-phenylalanine is incorporated in the seven position. Considering the differences in biological potency and the similarities in the NMR parameters between the linear and cyclic homologs, it can be concluded that the conformational properties that determine biological potency are too subtle to be measured by present NMR methodology. Furthermore, the similarity of the NMR shielding patterns suggests that a 23-membered ring is too large to impart significant conformational constraints on the peptide backbone or amino acid side chains.
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Preparation of deuterium labeled phenylalanine derivatives and the olid-phase peptide synthesis of [3-DL[α-²H₁]phenylalanine, 8-arginine]vasopressinKrupa, Timothy Stephen January 1979 (has links)
No description available.
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SYNTHESIS OF SOME BIOLOGICALLY ACTIVE PEPTIDESPowers, Stephen Palmer, 1948- January 1977 (has links)
No description available.
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Synthesis and oxidation studies of sulfur containing inhibitors for human leukocyte elastase : (2) synthesis of cyclic peptide analogs for tissue factor pathway inhibitor (TFPI) : Part 2 synthesis and evaluation of aziridinecarboxylic acid analogs as a new family of cysteine proteinase inhibitorsYamamoto, Masaru 08 1900 (has links)
No description available.
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HIV-1 subtype C gp41-based synthetic peptide constructs as potential vaccine componentsPhilippeos, Christina 28 April 2009 (has links)
M.Sc. / It is generally believed that the development of a completely effective vaccine for the human immunodeficiency virus (HIV) will likely require neutralizing antibodies that react with the diverse strains of cell-free forms of this virus, as well as induce cellular responses in the form of cytotoxic T-lymphocytes (CTL), to eliminate cell-associated virus. Vaccines based on viral envelope proteins attempt to induce the former response, whilst DNA/vector based approaches aim to induce CTL. The membrane proximal external region (MPER) of HIV-1 gp41 is a target of two broadly neutralizing human monoclonal antibodies, 2F5 and 4E10, and is an important lead for vaccine design. It is conserved among several strains of HIV-1, except for subtype C where restricted mutations are found, especially in the epitopes of 2F5 and 4E10. Mono- and polyvalent (homologous and heterologous) synthetic peptide constructs of the epitopes recognised by 2F5 and 4E10, based on HIV-1 subtype C, have been designed and their immunogenicity compared in this study. The peptide constructs, designated MPER 1 / 2, a / b, induced humoral immune responses in mice and rabbits with the use of adjuvants. The homologous constructs (designated a) induced better humoral immune responses than the heterologous versions (designated b) in small animals. However the antibodies generated in rabbits were not potent enough to neutralize isolates of HIV- 1. The induction of neutralizing antibodies may be addressed by further conformational considerations, as conjugation to an octameric lysine core was insufficient. The peptide constructs did induce proliferative and inflammatory immune responses in a murine model. Additionally, the peptide constructs were highly antigenic as neutralizing anti-HIV antibodies present in naturally infected sera were able to recognise and bind to the MPER peptides as antigen in ELISAs. This suggests that the peptide constructs may be of value for characterizing anti-MPER antibody responses in infected individuals. The constructs were further able to mimic the true representation of these regions in vivo, as human monoclonal antibodies 2F5 and 4E10 were able to recognize and bind 3 of the 4 constructs. The human anti-MPER antibodies as well as the recombinant monoclonal antibodies had a higher binding affinity for the heterologous constructs. The MPER constructs exhibited many beneficial characteristics and may therefore hold application as a component in HIV-1 preventative and therapeutic vaccination following further modification.
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HIV-1 subtype C envelope-based peptide constructs as potential vaccine components.Hewer, Raymond 09 May 2008 (has links)
The development of an effective HIV vaccine is hindered by several obstacles. One of the leading challenges is the antigenic variability of HIV-1 that is exhibited throughout all viral gene products but to greatest extent in the viral envelope proteins. This phenomenon is the result of continuous mutations in the HIV genome and is responsible for the immune escape of viral mutants. Many studies have suggested that a multivalent vaccine that elicits broadly cross-reactive antibodies is required to efficiently target antigenic variability. To this end, we have designed and analyzed a synthetic peptide construct that mimicked the major variability exhibited in the V3 loops of HIV-1 subtype C isolates. The peptide construct, described as a multiple epitope immunogen of the V3 loop with 8 branches and termed MEIV3b8, was shown to be non-toxic but highly immunogenic in experimental animals (mice and rabbits) and produced antibodies that were reactive to V3 loop peptides of various subtypes, variant envelope proteins and whole viral isolates [at antibody titers 1000 in enzyme-linked immunosorbent assays (ELISAs)]. Furthermore, functional antibodies were generated in rabbits that mediated neutralization of a neutralization-sensitive HIV-1 isolate and two distinct primary HIV-1 isolates in several different neutralization assays (at antibody titres 1213). Additionally, the MEIV3b8 induced both proliferative and inflammatory immune responses in a murine model.Finally, antibodies in the plasma of individuals (n = 148) infected with HIV-1 subtype C, subtype B and HIV-2 were found to bind to the MEIV3b8 as antigen in ELISAs. Through these findings, this study demonstrated that the variable MEIV3b8 effectively addressed antigenic variability and provided evidence that this peptide construct may hold application in HIV-1 preventative and therapeutic vaccination as well as HIV immunodiagnosis. / Dr. D. Meyer
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Synthesis and opioid activity of dynorphin analogues with the modifications in the message sequenceKulkarni, Sandhya N. 05 June 1995 (has links)
Graduation date: 1996
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