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1
Chen, Fei, and 陳飛. "Studies on aminoxy peptides and prebiotic peptide formation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38534149.
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Puchelle, Valentin. "Peptide-polymer conjugates : divergent synthesis from the initiating peptides." Electronic Thesis or Diss., Sorbonne université, 2020. http://www.theses.fr/2020SORUS472.
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L’utilisation de peptides pour des applications biomédicales reste limitée, en raison de leur courte demi-vie biologique. Le greffage de polymères aux peptides a conduit à l’amélioration des propriétés du peptide. Les conjugués peptide-polymère peuvent être synthétisés par méthode convergente ou divergente. Alors que la première approche conduit à de faibles rendements, la deuxième est limitée à la polymérisation de monomères vinyliques. Nous proposons une méthode de synthèse divergente des conjugués, basée sur la fonctionnalisation des liaisons peptidiques, via le greffage de polyéthers. En effet, la polymérisation anionique par ouverture de cycle (AROP) des epoxides, à partir d’amorceurs amide, à été démontrée. Cette méthode polyvalente donne accès à des chaines de type PEG sans activation préalable. Les fonctions NH des amides de peptides ont été déprotonnées par une base phosphazène pour générer un amorceur de l’AROP. Des dipeptides cycliques (DKP) ont d’abord été utilisés pour démontrer la fonctionnalisation des fonctions NH. Des conditions de polymérisation ont été identifiées pour synthétiser de manière contrôlée des chaînes de polymères fonctionnalisées par une DKP. Le même système d’amorçage a été appliqué à un dipeptide, et des conjugués ont pu être synthétisés. Des essais ont été menés sur un tripeptide protégé et non protégé, mais se sont révélés peu concluants<br>Peptides as drugs are facing drawbacks such as short in-vivo half life and low resistance to enzymes, which limits a larger scale use. To overcome these shortcomings, conjugation of polymers to peptides leads to improvements of pharmacokinetic properties of the peptide. Peptide-polymers conjugates are synthesized either by convergent or divergent synthesis. While the first strategy faces low yields, the second one is limited to vinyl-based polymers. We aim to functionalize peptides on amide bonds by divergent synthesis of polyether from the peptide. Anionic Ring-Opening Polymerization (AROP) of epoxides has already proven to be feasible, from amide-based initiators. The approach is polyvalent and gives access to PEG-like polymers without activation of peptides prior synthesis. In this project, NH amide functions from small peptides were deprotonated by phosphazene base to generate an AROP initiator. First, cyclic dipeptides, were used to demonstrate the possible functionalization on NH functions. Polymerization conditions were identified for a controlled AROP, to afford polymers end-capped by a DKP. Initiator’s complexity was increased to protected linear dipeptide. Similar initiating system was used as previously, and conjugates could actually be synthesized. Initiating capacities of tri-peptides and protected tri-peptides were also investigated but were found to be inefficient
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Swenson, Helen Rachel. "Studies in synthetic peptides and heterocyclic synthesis." Thesis, University of Edinburgh, 1999. http://hdl.handle.net/1842/13061.
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The following work documents three studies undertaken using solid phase synthesis techniques. Interaction of the zinc metalloprotease, endothelin converting enzyme-1(ECE-1), with its peptidic natural substrate big endothelum-1 has been investigated via an SAR study, using solid phase peptide synthesis (SPPS). Truncated forms of the substrate had been previously reported to inhibit ECE-1, this was confirmed however the big ET-1 analogues were shown to be substrates for the enzyme. A short study of the substrate specificity of ECE-1 was carried out. The synthesis of vast libraries of peptides using combinational synthesis has been used to accelerate the drug discovery process. Purification of these mixtures has not been previously attempted. 17-Tetrabenzo [a,c,g,i]fluoroeneyhethoxycarbonyl (Tbfmcc) developed for use with single peptides of proteins, has been used to achieve facile purification of five peptide libraries synthesised using SP. The methodology was fully optimised for the efficient separation of the desired library members from all impurities by exploiting the affinity of TBfmoc for carbon. A potential small molecule inhibitor of the zinc metalloenzyme, farnesyl transferase (FTase), was designed. The efficient solution phase synthesis of this novel structure is reported its adaptation to solid phase synthesis is described, with the view to using multiple parallel synthesis techniques to synthesise a range of analogous.
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Dillon, David Lawrence. "Peptide derivatives as pharmaceuticals : synthesis and reactions of n-thioacyl peptides." Thesis, Oxford Brookes University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327912.
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Lam, Hiu-yung, and 林曉勇. "Total synthesis of daptomycin and other cyclic peptides via Ser/Thr ligation-mediated peptide cyclization." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/207198.
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Head-to-tail cyclic peptides with a wide range of ring sizes have been discovered in various organisms including bacteria, fungi, plants and animals. Many of them exhibit remarkable biological activities with high potency. Daptomycin, a cyclic lipodepsipeptide isolated from soil bacteria Stretomyces roseoporus, is the first natural product antibiotic launched in a generation. Daptomycin has potent bactericidal activity against otherwise antibiotic-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and vancomycin-resistant S. aureus. Daptomycin contains a 31-membered ring made up of 10 amino acids and a linear 3-amino acid side chain modified with an n-decanoyl lipid at the N-terminus. The complex structure of daptomycin, the presence of two non-proteinogenic amino acids (kynurenine and 3-methyl glutamic acid) and the macrolactamization of a 31-membered ring render daptomycin a challenging target for total synthesis. We recently developed a chemoselective serine/threonine ligation (STL) allowing peptide ligation at Ser/Thr site using side chain unprotected segments. We have successfully applied STL intramolecularly in the key cyclization step for the synthesis of daptomycin molecule, which allows us to finally achieve the first total synthesis of daptomycin. With this technique in hand, the chemical synthesis of daptomycin analogues, which are difficult to obtain otherwise becomes possible and is now ongoing. This would allow for the search for optimized analogues.
We further investigated if STL could be applied for the synthesis of cyclic tetrapeptides, which are extremely difficult to be synthesized in the absence of turninducing components due to their rigid structural framework. To our delight, a series of cyclic tetrapeptides without any turn-inducing component, like Gly, Pro or Damino acids have been successfully synthesized by intramolecular STL. The synthesis of cyclic tetrapeptides with drug-like scaffold would be useful for the therapeutic development. We also applied intramolecular STL to successfully synthesize some natural cyclic peptides with different ring sizes, including anticancer stylopeptide 1, phakellistatin 4 and anti-inflammatory cyclosquamosin D.<br>published_or_final_version<br>Chemistry<br>Doctoral<br>Doctor of Philosophy
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Corrihons, Fabien. "Solid phase peptide synthesis of cyclic peptides for cancer oncology." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424312.
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Ndung'u, Susan Wanjiru. "The medicinal chemistry of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro)." Thesis, Nelson Mandela Metropolitan University, 2011. http://hdl.handle.net/10948/7083.
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Although peptides and proteins are considered as lead compounds for the discovery and development of new therapeutic agents, poor metabolic and physical properties have limited their optimisation as drug candidates (Adessi & Soto, 2002). Research by medicinal chemists however, generated the discovery of structural similarities between some peptides and diketopiperazines and the common occurrence of such compounds in natural products. This discovery initiated the synthesis of diketopiperazines from amino acids in an attempt to bypass the previously mentioned limitations of using peptides as drug candidates (Dinsmore & Beshore, 2002). Diketopiperazines (DKPs) are the simplest form of cyclic dipeptides, and a class of unexplored bioactive peptides that have great potential for the future. The compounds are relatively simple to synthesise and are prevalent in nature (Prasad, 1995). The DKP backbone is rigid and therefore poses conformational constraint on the compounds. This rigidity allows for simple conformational analysis of the compounds and also gives insight into the conformational requirements for interaction with the targets involved in their biological activity. The reduced conformational freedom also increases the receptor specificity and thus the compounds are proposed to have less unfavourable effects (Anteunis, 1978). The aim of the study was to synthesise compounds that would exhibit metabolic stability, receptor specificity and enhanced lipophilicity which would increase the bioavailability of the compounds. This was to be achieved by the introduction of fluorine and chlorine elements into the DKPs. The structure of the DKPs would be altered which in turn would improve the physicochemical properties and the biological activity of the compounds (Naumann, 1999). Cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) were synthesised using the method of Milne et al. (1992) and by boiling the linear counterparts under reflux in sec-butanol-toluene. The structures of the synthesised DKPs were elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and molecular modeling. Qualitative analysis and evaluation of the physicochemical properties of the DKPs were performed using high-performance liquid chromatography, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry and x-ray powder diffraction. The study aimed to determine the biological activity of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) with respect to their anticancer, antimicrobial, haematological and antidiabetic effects. The anticancer results obtained indicated that the percentage inhibition produced by both DKPs were lower than those proposed by Graz et al. (2000) for proline-containing DKPs where, a greater than 50% inhibition was observed for cyclo(Phe-Pro). Antimicrobial studies revealed that both DKPs demonstrated marginal effects on Gram-positive and Gram-negative organisms but showed significant effects against C. albicans. The haematological studies revealed that cyclo(D-Phe-2Cl-Pro) at a screening concentration of 12.5 mM, significantly decreased the levels of D-dimer (P < 0.0001). The antidiabetics studies showed limited activity of the DKPs in inhibiting the activity of α-glucosidase and α-amylase enzymes.
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Sieber, Stephan Axel. "Nonribosomal peptide synthetases quaternary structure and chemoenzymatic synthesis of macrocyclic peptides /." [S.l.] : [s.n.], 2004. http://archiv.ub.uni-marburg.de/diss/z2004/0218/.
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Irving, Stephen L. "Synthesis and purification of peptides." Thesis, University of Edinburgh, 1994. http://hdl.handle.net/1842/28282.
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Improved routes to tetrabenz[<I>a,c,g,i</I>]fluorene derivatives have been developed, allowing the synthesis of N<SUP>α</SUP>-17-tetrabenzo[<I>a,c,g,i</I>]fluorenyl-methoxycarbonyl (tbfmoc) urethane derivatives of alanine, leucine, isoleucine, methionine and valine. The chloroformate and pentafluorophenyl carbonate of 17-tetrabenzo[<I>a,c,g,</I>]fluorenylmethanol have been prepared and used to introduce the base-labile Tbrmoc group onto the N<SUP>α</SUP>-termini of resin-bound peptides. The high affinity of the Tbrmoc group for porous graphitised carbon (PGC) has been exploited for the purification of a range of synthetic peptides (23-85 residues). A comparison of various basic solvent systems used to elute the purified peptide from PGC is presented. The hydrophobicity of the Tbfmoc group has been used to simplify the purification of a ubiquitin analogue, UbY59F (76 residues), by the enhanced retention of the Tbfmoc peptide on RP-HPLC. A new synthesis of 2-hydroxydibenzocycloheptadien-5-one has been advised. This compound has been used to develop acid-labile linkers for the synthesis of peptide C-terminal alkyl amides and aza-glycine peptides, compatible with the Fmoc/<SUP>t</SUP>Bu solid phase method. Alternative modes of attachment of the linker to polystyrene resin are compared for the synthesis of bombesin, a peptide amide.
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Alexander, Mcmanamara Linda Mary. "Synthesis of stable - helical peptides." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398920.
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Martari, Marco. "Structure-function relationships of bolaamphiphilic peptides and peptide hybrids." Thesis, Link to the online version, 2006. http://hdl.handle.net/10019/582.
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Rutt, Jason E. "The synthesis of marine cyclic peptides." Thesis, University of Nottingham, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262984.
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Tyszka, Joanna Helen Margaret. "Towards the synthesis of polycyclic peptides." Thesis, University of York, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282302.
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Bennett, Fiona Catherine. "Design and synthesis of model peptides." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299882.
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Ahadi, Sara. "Ribosomal Synthesis of N-methylated peptides." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/134.
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Natural peptide products isolated from various organisms often contain N-methylated backbones. Such a modification of backbone of the peptide changes its conformational rigidity. This modification improves the biological properties of the peptide, such as improved target affinity, proteolytic stability or membrane permeability. Therefore synthesis of N-methylated peptide libraries is valuable in screening for drug-like peptides suitable for therapeutic uses. Protein synthesis using recombinant elements (PURE) and Flexizyme were used in order to reassign specific codons to N-methyl amino acids. mRNA-dependent translation system enable us to make our desired peptides with N-methyl amino acids. This technology is a convenient tool for the construction of N-methyl peptide libraries. Using Flexizyme in order to make library of N-methyl peptides requires significant amount of tRNA. Therefore developing a simple and rapid method for purification of specific tRNA from fully modified E. coli total tRNA would be advantageous Here we reported a new technique in purification of individual tRNAs using fluorous affinity tag. From total tRNA, desired tRNA could be charged with related amino acid and tagged with fluorous molecule through reductive amination.
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Hone, Neal. "The synthesis of atypical amino acids and peptides utilizing solid phase peptide synthesis and novel amine protection." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357925.
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Taylor, Tammye L. "UV photochemistry of synthetic model peptides." Thesis, Georgia Institute of Technology, 1994. http://hdl.handle.net/1853/26966.
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Lobo, Ruiz Ariadna. "Pushing peptides further: Novel methodologies for the synthesis of backbone-modified peptides." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667017.
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Peptides and proteins are essential substances for living organisms, as they can be found in every cell and tissue and are involved in many biological and physiological processes. Given their intrinsic properties and their attractive pharmacological profile, they have emerged as potential tools for drug discovery. However, in vivo instability due to protease degradation and poor bioavailability are the main drawbacks that have hampered their exploitation as therapeutic agents. Of special interest are peptide-based molecules displaying peptide backbone modifications, since they often result in improved pharmacological properties, such as greater stability and bioavailability, enhanced cell permeability and lower toxicity. Among the most relevant types of bioactive backbone-modified peptide families, depsipeptides and stapled peptides are included. In this context, the work presented herein was focused on the development of novel methodologies for the synthesis of depsipeptides and stapled peptides. Up to date, the most general and effective strategy for the preparation of complex cyclodepsipeptides combines solid-phase synthesis and solution chemistry approaches, in which segment condensation is used for the assembly of the building blocks containing the depsipeptide moieties. However, this methodology presents some disadvantages. For instance, the synthetic route must be designed and optimised for each particular case, and therefore a versatile general synthetic method cannot be outlined. Thus, a robust full solid-phase methodology would become a valuable chemical tool for both the preparation of naturally-occurring cyclodepsipeptides and the rapid generation of synthetic analogues. With that purpose, a synthetic analogue of naturally-occurring cyclodepsipeptide YM-254890 was used as a model depsipeptide for the development of such methodology, where the drawbacks commonly encountered during solid-phase depsipeptide synthesis, including: DKP formation, formation of undesired α,β-elimination side-products during Fmoc removal and selection of the optimal protecting group scheme, were extensively studied and solved. Additionally, evaluation of the strategy efficiency was carried out by comparison with conventional segment condensation approaches. Remarkably, similar overall yields as the ones obtained for segment condensation approaches were observed. Thus, the newly developed methodology becomes a versatile and convenient tool for the preparation of complex cyclodepsipeptides. On the other hand, great efforts have been put into the
generation of novel stapled peptides mimicking α-helices. Although extensive research has been carried out in this field, a single universal stapling technique cannot be established, since selection of the most suitable cross-linking approach highly depends on the nature of the protein-protein interaction to be addressed. Nevertheless, the ability of stapled peptides to cross the cell membrane, increase in vivo stability and exhibit improved biological activity, has gained raising interest over the past years. It is well known, that backbone N-modified peptides exhibit greater lipophilicity, which ultimately results in enhanced cell internalisation. Additionally, N-modified peptides present higher resistance against proteolytic degradation. Considering these benefits, we envisioned that insertion of N-methyl-rich peptide bridges would be a good approach to develop a novel class of stapled peptides with an enhanced pharmacokinetic profile. With that purpose, the second part of this work was addressed at the design and development of a novel class of single and double highly N-methylated stapled peptides, or the so-called HMSP. Due to the importance of the p53 tumour suppressor, which activates cell death in response to various stress conditions, the p53-MDM2 protein- protein interaction was the focus in the development of our synthetic methodology. To linear p53-based peptides presenting a random coil secondary structure, several N- methyl-rich peptide bridges of different nature and length were inserted at different positions. Insertion of these staple entities makes these molecular constructs highly versatile, as the nature, length and flexibility of the staple can be modulated by the number and nature of NMe-amino acids. Circular dichroism experiments confirmed that helicity was induced, and allowed evaluation of the helicity increase for each system.<br>Dadas sus propiedades intrínsecas y su atractivo perfil farmacológico, los péptidos y las proteínas, surgen como potenciales agentes terapéuticos para el descubrimiento de nuevos fármacos. No obstante, su explotación en este campo ha sido obstaculizada por su escasa estabilidad y biodisponibilidad. De especial interés, son las modificaciones en el esqueleto peptídico, ya que a menudo dan lugar a propiedades farmacológicas mejoradas, tales como una mayor estabilidad, biodisponibilidad, permeabilidad celular y una menor toxicidad. La presente tesis se centra en los depsipéptidos y péptidos grapa, que se encuentran entre las familias de péptidos más relevantes que presentan modificaciones en el esqueleto peptídico. En el primer proyecto, se desarrolló una metodología robusta en fase sólida, basada en la estrategia Fmoc, para la preparación de depsipéptidos que contienen enlaces éster múltiples y consecutivos. Para ello, un análogo sintético del ciclodepsipéptido natural YM-254890 se designó como modelo para estudiar los inconvenientes comúnmente encontrados en la síntesis de depsipéptidos en fase sólida, que a día de hoy, han obstaculizado la instauración de dicha metodología. Por consiguiente, dificultades como la formación de DKP, la eliminación problemática de Fmoc, la selección del esquema de grupos protectores, entre otras, fueron ampliamente estudiadas y resueltas. En el segundo proyecto, con el fin de inducir la conformación hélice alfa, a la vez que preparar compuestos con un perfil farmacológico mejorado, se abordó el diseño y desarrollo de una nueva clase de péptidos grapa altamente N-metilados, los denominados HMSP. Para ello, entre dos posiciones clave de la secuencia bioactiva del péptido p53, que naturalmente no presenta una estructura secundaria organizada, se introdujeron varios péptidos puente ricos en residuos N-metilo. La estructura hélice alfa fue inducida satisfactoriamente. Por otro lado, la inserción de dichos puentes dio lugar a la preparación de construcciones moleculares altamente versátiles, dado que la naturaleza, la longitud y la flexibilidad del puente pueden ser moduladas por el número y la naturaleza de los aminoácidos N-metilados.
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Allen, William M. "Synthesis and characterization of novel phosphonopeptides /." Connect to online version, 1997. http://hdl.handle.net/1989/3742.
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Stewart, A. S. J. "Organometallic derivatives of amino acids and peptides." Thesis, Robert Gordon University, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376684.
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Deshmukh, Manjeet Vinayakrao. "Synthesis and characterization of mussel adhesive peptides." [S.l. : s.n.], 2005. http://archiv.ub.uni-marburg.de/diss/z2005/0111/.
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Brown, Angus R. "Solid phase synthesis of peptides and proteins." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/27313.
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A strategy for the total chemical synthesis and purification of proteins has been investigated and applied to the 85 residue methylated DNA binding domain (MBD) from the chromosomal protein MeCP2, the 66 residue Restriction Alleviation (Ral) protein from bacteriophage λ and the 76 residue β-chemokine Monocyte Chemotactic protein (MCP-1). The hydrophobicity of the N<SUP>α</SUP> protecting group tetrabenzo[a,c,g,i]fluorenyl-17-methoxycabonyl (Tbfmoc) has been exploited to simplify the rapid purification of the 85 amino acid MBD protein by Hplc. Initial structural studies on the synthetic protein are also reported. In addition a comparative study of semi-permanent, temporary and enzyme cleavable thiol protection has resulted in the extension of this Tbfmoc methodology to the synthesis of cysteine containing proteins such as Ral and MCP-1. A general route to C-terminal α-hydroxyglycine extended peptides via Fmoc/t-Bu based solid phase peptide synthesis is also described. Such peptides are the biosynthetic precursors of peptide amides in which the C-terminal carboxamide functionality is required for biological activity in a number of important hormones.
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Cutts, Rosalind Jennifer. "Modelling, NMR and synthesis of food peptides." Thesis, University of Surrey, 1996. http://epubs.surrey.ac.uk/842985/.
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The work in this thesis can be divided into two sections, namely the study of delicious peptide, a food flavour and the antimicrobial peptide lactofenicin B. The main interest in these compounds is in terms of structure and conformation adopted in solution and how this relates to their mode of action. Delicious peptide was studied initially by 1H NMR spectroscopy for evidence of a specific solution structure. Results show that delicious peptide does not adopt a regular conformation in solution. Molecular dynamics simulations of this peptide show the flexibility of the peptide structure in solution. Quenched molecular dynamics simulations were used to search for low energy conformers of the peptide. The results suggest that the flavour of the peptide is produced by interaction of basic and acidic regions in the peptide. The work was extended to examine delicious peptide analogues with similar flavour characteristics. The results obtained suggest that similar interactions of basic and acidic regions occur for these peptides to produce a savoury flavour. The antimicrobial peptide Lactofemcin B was synthesised by Fmoc poly-amide synthesis. Problems with the synthesis occurred due to the protecting groups used for the five arginine residues present in the sequence. Predictive modelling studies on Lactofenicin B peptide, derived from bovine lactofenicin protein suggest that the peptide adopts a region of alpha-helical conformation in solution. The flexibility of the peptide was studied by molecular dynamics in solution and simulations of other environmental conditions were carried out by variation of electrostatic interactions using dielectric constants for membrane, TFE and water environments. The results suggest the beta-helical conformation is most stable in an environment such as trifluoroethanol, the peptide showing more flexibility in aqueous solution. Experimental results for the peptide confirm the flexibility of the peptide in solution. CD results show that lactofenicin B has no specific conformation in solution, although an beta-helical conformation is adopted in trifluoroethanol. The peptide also adopts a beta-sheet conformation in low concentrations of SDS micelle and therefore its conformation is dependant on environmental conditions. NMR studies show that the peptide, although flexible in solution, shows short-range NOE interactions that suggest a local beta-helical conformation may be present. However the overall conformation for the peptide is a flexible one.
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Andrews, Martin James Inglis. "Design and synthesis of conformationally stabilised peptides." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264663.
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Zambrano, Raúl Horacio. "Synthesis and structural studies of prion peptides." Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/36652.
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Jiang, Lu. "Chemical synthesis of peptides with biological importance." Thesis, University of Edinburgh, 1996. http://hdl.handle.net/1842/12302.
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Al-Wafi, Haider. "Synthesis and biological studies of cyclic peptides." Thesis, Cardiff University, 2018. http://orca.cf.ac.uk/114900/.
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Bax peptide 1c (FLIMGWTLD) and two of its derivatives, 15-mer cyclic peptide 2c (FLRELIRTIMGWTLD), 13-mer cyclic peptide 3c (FLKSSKIMGWTLD) with their linear counterparts (1b, 2b, 3b) were prepared by a head−to−tail cyclisation strategy, purified (HPLC), characterised and identified (LCMS). Then the mass and concentration of the two derivatives (2c, 3c) with their linear counterparts (2b, 3b) were calculated. MS2 mass spectra were used as evidence of synthesis of the cyclic peptides from their linear counterparts. There was a clear difference between each of the two cyclic peptides and its linear counterpart’s mass spectra. A peak appeared for a fragment which has the two termini bonded together (Phe−Asp) in the cyclic peptide spectrum (1c, 2c, 3c) that did not appear in the linear peptide spectrum (1b, 2b, 3b). The enzymatic degradation and kinetic study were undertaken for just the two derivatives (2c, 3c) with their linear counterparts (2b, 3b) using trypsin and chymotrypsin. Compound 1c and its linear counterpart (1b) were excluded from these two studies and the stability studies of the peptide in fetal calf serum (FCS) medium because the 9-mer cyclic peptide (1c) had very low solubility in HPLC solvents and was hydrolysed during storage in the freezer. Chymotrypsin cleaved the peptide bond between Trp and Thr but did not cleave the peptide bond between Phe and Asp in the 15-mer cyclic peptide (2c) and its linear counterpart (2b). Cyclisation of the linear peptide (2b) did not improve the stability of the peptide as the t1⁄2 of the cyclic peptide (2c) was less than the t1⁄2 of its linear counterpart (2b). Trypsin cleaved the peptide bond between Arg and Thr in the linear peptide (2b), while in the cyclic peptide (2c) the cleavage was between Arg and Thr in addition to Arg and Glu. Stability of the cyclic peptide (2c) did not improve significantly as the t1⁄2 of compound 2c increased slightly in comparison to the t1⁄2 of its linear counterpart (2b). The effect of chymotrypsin on the two peptides (3b, 3c) was the same. The peptide bond between Trp and Thr was hydrolysed in the two compounds (3b, 3c), while between Phe and Leu did not break. Cyclisation of the linear peptide (3b) did not improve the stability of the peptide because the t1⁄2 of the cyclic peptide (3c) increased slightly in comparison to the t1⁄2 of its linear counterpart (3b). There was significant stability for the cyclic peptide (3c) against trypsin in comparison to its linear counterpart (3b). Compound 3c did not hydrolyse for 30 min, while compound 3b was hydrolysed at the peptide bond between Lys and Ile in the first few minutes of the enzymatic hydrolysis. The stability of 15-mer cyclic compound (2c) was less than its linear counterpart (2b) in the medium of fetal calf serum (FCS) as the t1⁄2 of compound 2c (120 h) was less than the t1⁄2 of compound 2b (165 h). In contrast, the stability of the 13-mer cyclic compound (3c) was more than its linear counterpart (3b) as indicated by the t1⁄2 of compound 3c (285 h) that was more than the t1⁄2 of 3b (110 h).
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Fletcher, Matthew David. "Tailored peptides : the synthesis and conformational behaviour of partially modified retro-inverso peptides." Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760695.
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Kumari, P. "New methods for the conjugation of peptides." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279720.
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Wong, Kim Kai Wai. "Synthesis of silicon functionalised cyclic peptides for enantiomeric separations." Thesis, University of Bath, 1990. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278284.
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Findlay, Brandon. "Design and synthesis of cationic amphiphiles." American Society for Microbiology, 2010. http://hdl.handle.net/1993/21708.
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Cationic antimicrobial peptides (CAMPs) are produced by plants, animals and bacteria to protect their host against antagonistic microbes. The antitheses of selective antibiotics, these peptides are drawn by electrostatic and hydrophobic interactions to targets as diverse as the bacterial membrane, nucleic acids and serum proteins. This lack of specificity is their greatest strength, as mutations to single genes rarely lead to bacterial resistance. Resistance may be conferred by large scale alterations in cell envelope composition, which generally reduces bacterial fitness in the absence of peptide.
Clinical applications of natural CAMPs are limited, as the peptides are toxic to mammalian cells and rapidly inactivated in vivo by serum albumin and proteases. Faced with these challenges we have prepared a number of CAMP analogues, with the goal of creating lead compounds for further development of antibacterial therapeutics. Much of our work has focused on ultrashort lipopeptides and lipopeptoids, which have properties similar to natural CAMPs and extremely abbreviated sequences. The simple structure of these scaffolds allows rapid creation of CAMP analogues in a brief period of time, allowing us to rapidly explore the structural requirements for CAMP activity. The balance of this work focuses on imparting CAMP-like behaviour to known antibiotics, in order to expand their spectrum of susceptible bacteria and combat the development of drug-resistant bacteria. In particular, the aminoglycosides neomycin and tobramycin have been fused to phenolic disinfectants such as triclosan and biclotymol, in order to improve their diffusion across the bacterial envelope and activity against Gram-negative bacteria.
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Shi, Feng, and 石峰. "Synthesis, characterization and application of constrained 7/8 helix." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44363229.
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In this thesis, constrained 7/8 helix has been developed to enhance the stability of 7/8 helical structure in polar and aqueous solvents for biological application.
The synthesis of constrained 7/8 helical peptides has been achieved in two steps. In the first step, a 7/8 helical peptide chain comprising alternating α-L-amino acids and α-D-aminoxy acids was assembled by standard solution phase peptide synthesis protocol. In the second step, a covalent cross-linker as the conformational constraint was incorporated into 7/8 helical peptide at adjacent α-amino acid residues by consecutive intramolecular ring-closing olefin metathesis reaction and catalytic hydrogenation reaction.
Conformational properties of constrained 7/8 helical peptides have been explored by applying NMR spectroscopy, theoretical calculation, and circular dichroism spectroscopy to three constrained tetrapeptides 2.2–2.4 and one non-cross-linked reference peptide 2.1. It was discovered that constrained 7/8 helical peptides with a saturated methylene chain as the covalent cross-linker maintained the structural feature of alternating N–O turns and γ-turns, and exhibited increased stability in both organic solvents and aqueous media. No obvious difference was observed for the covalent cross-linker with six, seven, or eight methylene units in improving the stability of 7/8 helix.
The constrained 7/8 helix with enhanced structural stability was applied in the design of α-helix mimics. Based on the structure of helix D in the crystal structure of CD81 large extracellular loop, the putative receptor of Hepatitis C Virus envelop 2 (HCV E2) protein, constrained 7/8 helical hexapeptides 4.1 and 4.2 with free N-terminus were designed and synthesized in the form of TFA salt as the candidates of helix D mimics. It was expected that peptides 4.1 and 4.2 could act as the inhibitors of the interaction between helix D and HCV E2 to block HCV entry into cells. Unfortunately, the biological activity test on the ability of peptides 4.1 and 4.2 in HCV inhibition revealed that none of these peptides exhibited detectable inhibitory effect on the entry of HCV into cells and HCV replication at the concentration of 100 μM.<br>published_or_final_version<br>Chemistry<br>Doctoral<br>Doctor of Philosophy
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Freeman, David J. "Synthetic and metal binding studies of cyclic peptides." Thesis, University of Nottingham, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299566.
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Varedian, Miranda. "Photoswitchable Peptidomimetics : Synthesis and Photomodulation of Functional Peptides." Doctoral thesis, Uppsala universitet, Institutionen för biokemi och organisk kemi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9345.
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The secondary structure of peptides is of pivotal importance for their biological function. The introduction of photoswitchable moieties into the backbones of peptides provides a unique way of regulating their conformation using an external stimulus, i.e., light. This thesis addresses the design, synthesis, and conformational analysis of photoswitchable peptidomimetics (PSPM). Examples of photomodulation of their functional properties are given. PSPM were prepared by incorporation of stilbene and thioaurone chromophores (switches) into dipeptides. Synthetic schemes for preparing these chromophores have been developed. Their suitability for incorporation into peptidomimetics has been demonstrated, and the resulting PSPM have been subjected to photoisomerization as well as computational and spectroscopic conformational analysis. The chromophore’s potential as a β-hairpin inducer was particularly interesting. To investigate the factors that govern the formation of β-hairpins, a series of decapeptides were prepared. Turn regions consisting of amino acids or chromophores were combined with antiparallel peptide strands with hydrophobic side chains. Linear tryptophan zipper peptidomimetics and cyclic peptidomimetics with a second, hairpin-inducing turn region were particularly promising. Comparison between switches revealed that the more flexible stilbene is a better choice for upholding the β-hairpin conformation than the thioaurone. The catalytic properties of an artificial hydrolase with a helix-loop-helix structure can be improved by introducing a stilbene photoswitch into the loop region. Photoisomerization regulates the catalytic activity of this peptidomimetic, and provides a means to control its aggregation state. The activity of the enzyme Mycobacterium tuberculosis ribonucleotide reductase was realized by incorporating a stilbene moiety into a linear peptide. Here, one photoisomer proved to be an inhibitor at nM concentrations. A significantly lower effect was observed for the other isomer. Finally, the decomposition of thioaurones, mainly to thioflavonols and thiaindenes, under conditions used for solid-phase peptide synthesis has been mapped. These findings are expected to have implications for future use of this chromophore.
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Tegazzini, Diana. "Design, synthesis and activity evaluation of antioxidant peptides." Thesis, Queen's University Belfast, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603073.
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Reactive Oxygen Species (ROS) produced during normal aerobic metabolism, if not promptly removed by the detoxification mechanisms of the cells, can easily react with cell components, especially lipids, producing secondary cytotoxic molecules called reactive carbonyl species (RCSs). RCSs exhibit significant chemical reactivity and can cause protein modification and dysfunction. One of the most important ReSs is 4-hydroxinonenal (HNE), an unsaturated aldehyde that has been strongly linked to Alzheimer'S disease (AD). A new series of dipeptide histidyl hydrazide analogues of carnosine was prepared, with the aim of producing molecules with enhanced HNE scavenging activity. These compounds were demonstrated to scavenge HNE and to protect SH-SY5Y cells from HNE-induced tOxlcity and were superior in action to carnosine. The synthesis of an analogue of the best compound of the series containing caffeic acid, resulted in the generation of a new molecule exhibiting complete retention of HNE-scavenging activity and also possessing free Radical Scavenging Activity (RSA). Mitochondria are the major sites of high levels of oxidative stress and the targeting of a reactive carbonyl scavenger directly to these organelles would result in extinguishing the primary source of RCS, thus arresting any consequent cellular damage. In the present work, the possibility of specifying the cellular localization of histidyl hydrazide was investigated using previously described mitochondria penetrating peptides (MPPs) and new examples of such sequences I modified to be more resistant to protease degradation. The ligation of histidyl hydrazide to a previously reported MPP was successful in targeting the former to the mitochondria of HeLa cells. Finally. a particular chemical ligation approach was investigated for the development of a system of linking a common peptide vector and a variety of cargo molecules of choice through facile in situ coupling, without requiring the de novo synthesis of a new chemical conjugate in each instance.
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Cammish, Linda E. "The solid phase synthesis of arginine containing peptides." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328560.
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Roach, Peter L. "Synthesis of peptides by the solid phase method." Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/14289.
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An investigation into the use of a novel N<SUP>PROB*LEM</SUP> protecting group in peptide synthesis is described. The protecting group, 2,2-<i>bis</i>(4'-nitrophenyl)ethoxycarbonyl (Bnpeoc), has been introduced into the full range of amino acids, including those requiring appropriate side chain protection. The Bnpeoc amino acid derivatives have been successfully applied to the solid phase synthesis of a number of peptides from ubiquitin. In addition, the peptides were assembled using a wide range of coupling reagents and conditions. The chemical syntheses of phage λ Cro protein and peptides from its DNA binding region have also been investigated, using both the novel N^PROB*LEM-Bnpeoc protecting group and the established N^PROB*LEM-fluorenylmethoxcarbonyl (Fmoc) protecting group. N.m.r. experiments have indicated that residues corresponding to the DNA recognition α-helix of the Cro protein may adopt a similar conformation in a peptide from that region.
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Lear, Sam. "Total synthesis of bioactive peptides and whole proteins." Thesis, Durham University, 2016. http://etheses.dur.ac.uk/11946/.
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Total chemical synthesis is an essential tool for the validation of natural product structures and the discovery and elaboration of novel therapeutic scaffolds. Chapter 1 (Part I) surveys existing treatments for trypanosomatid neglected tropical diseases, and the synthesis of a novel class of antiparasitic cyclic depsipeptides is reported (Chapter 2) alongside a full NMR assignment and structure calculation using NMR-derived distance restraints. The synthetic peptides exhibit activity profiles in agreement with published results, and a series of ester-to-amide substitution analogues also synthesized show similar low micromolar potency. Chapter 3 describes the synthesis of lassomycin, a tuberculocidal lasso peptide reported to exhibit a unique unthreaded topology. The naturally occurring peptide was synthesized alongside C-terminally amidated and truncated analogues, but none were biologically active. Given clear differences observed in the two-dimensional NMR data for synthetic lassomycin, it is suggested that the reported natural product in fact exists in the threaded form. The chemical synthesis of whole proteins is addressed in Part II, and current progress in the field is reviewed (Chapter 4). Work towards the total chemical synthesis of acyl carrier protein using a two fragment approach is described in Chapter 5. The N-terminal fragment was synthesized using the sulfonamide linker, and while the C-terminal fragment presented difficulties due to extremely low solubility, solubilization using backbone protection was demonstrated. The development of a modified Dawson linker for the synthesis of peptide N-acylureas without overacylation is also described. Finally, Part III details the synthesis of tumor targeting peptides used for imaging and inhibition of cancer cell growth, and which cause tumor size reduction in vivo. A novel web utility used for the automated assignment of peptide mass spectra throughout this thesis is also presented.
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Tamura, Takashi. "Synthesis and Biochemical Function of Selenocysteine-containing Peptides." Kyoto University, 1993. http://hdl.handle.net/2433/168917.
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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものである<br>Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(農学)<br>甲第5495号<br>農博第775号<br>新制||農||660(附属図書館)<br>学位論文||H5||N2607(農学部図書室)<br>UT51-93-R23<br>京都大学大学院農学研究科農芸化学専攻<br>(主査)教授 左右田 健次, 教授 浅田 浩二, 教授 清水 昌<br>学位規則第4条第1項該当
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Foster, Michael Scott. "Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/31816.
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Thesis (Ph.D)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009.<br>Committee Chair: Dr. Sheldon W. May; Committee Member: Dr. James C. Powers; Committee Member: Dr. Nicholas Hud; Committee Member: Dr. Niren Murthy; Committee Member: Dr. Stanley H. Pollock. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Nowak, Cheryl L. "Design, synthesis, and evaluation of bicyclic peptides as ammonium ionophores." Link to electronic thesis, 2003. http://www.wpi.edu/Pubs/ETD/Available/etd-0428103-180827/.
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Thesis (M.S.)--Worcester Polytechnic Institute.<br>Keywords: solution 13C-NMR study; olid phase peptide synthesis; bicyclic peptides; ammonium ionophores; valinomycin; ion selective electrode. Includes bibliographical references (p. 63-65).
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Sasubilli, Ramakrishna Gutheil William G. "Solid-phase synthesis of peptides and peptide mimetics using urethane and backbone amide linker strategies." Diss., UMK access, 2006.
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Thesis (M.S.)--School of Pharmacy. University of Missouri--Kansas City, 2006.<br>"A thesis in pharmaceutical sciences." Typescript. Advisor: William G. Gutheil. Vita. Title from "catalog record" of the print edition Description based on contents viewed Nov. 9, 2007. Includes bibliographical references (leaves 63-73). Online version of the print edition.
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Umeobika, Ugochukwu Christian. "Solid phase peptide synthesis of substrates for the chemoenzymatic generation of cyanobactins analogues." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=233678.
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Ribosomal synthesized and post translational modified peptide natural products have attracted a lot of interest in the past decade. Backbone cyclization of the translated linear peptides is generally catalysed by specific enzymes giving them peptidase resistance, thermodynamic stability and various other physiological activities. These features have made backbone cyclic peptide to become an attractive resource for drug discovery. Here, we described the synthesis of linear peptides containing natural and unnatural residues and its biosynthetic mechanism to generate man-made cyclic peptides. In this thesis we used SPPS to make short and medium linear peptide chains, we purified them using HPLC, and analysed them using MS. We incorporated unnatural residues such as homocysteine, homoserine, aminoalanine, propargyl glycine and the substrates were subjected to different enzymatic reaction such as prenylation, heterocyclization and macrocyclization modification reactions to generate small macrocycles (4-6 residues), prenylated linear peptides, and patellamime analogues. The final products were analysed using LC-MS. In our results, we verified that kawaguchipeptin (kgp) gene cluster is responsible for the production of kawaguchipeptins through heterologous expression of the kgp gene cluster in Escherichia coli. The KgpF prenyltransferase was overexpressed and was shown to prenylate C-3 of Trp residues in both linear and cyclic peptides in vitro. We also found out that PatGmac can macrocyclise short peptides (4-6 residues) to generate small macrocyclic peptides. We also tested the flexibility of OscGmac using unnatural amino acid residues such as pseudoprolines and pipecolic acid that can mimic the heterocyle incorporated as the final residue in the natural product. Our results show that OscGmac recognises pseudoprolines before AYD(G) to process a linear peptide.
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Hao, Yu, and 郝宇. "Synthesis and conformational studies of beta 2,3-cyclic aminoxy peptides." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B36363236.
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Cassidy, Peter Joseph. "The design and synthesis of peptide turn mimetics /." St. Lucia, Qld, 1998. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16396.pdf.
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Ng, Choi I.-teng Montserrat. "Solid-phase synthesis of 5-arylhistidine-containing peptides: from linear antimicrobial peptides to cyclic peptides derived from arylomycins and aciculitins." Doctoral thesis, Universitat de Girona, 2015. http://hdl.handle.net/10803/380739.
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The incorporation of unsymmetrical biaryl systems into peptide sequences is a strategy that can improve their biological activity. Due to the difficulty of arylating the 4(5}-position of the imidazole ring, this doctoral thesis was focused on the development of efficient methodologies for the solid-phase synthesis of 5-arylhistidine-containing antimicrobial undecapeptides through a Suzuki-Miyaura reaction under microwave irradiation. The extension of this protocol allowed the preparation of biaryl cyclic peptides of different ring sizes bearing a His-Phe or His-Tyr biaryl linkage. Then, it was developed a procedure for the total solid-phase synthesis of biaryl cyclic lipopeptides derived from arylomycins. These strategies were extended to the preparation of biaryl cyclic analogues of the marine bicyclic pptides aciculitins. In particular, it was achieved the synthesis of analogues of the northern and the southern hemispheres of aciculitins as well as biaryl bicyclic peptides incorporating a Phe-Phe, a Phe-Tyr, a His-Tyr or a Tyr-Tyr biaryl bridge<br>La incorporació de sistemes biarílics asimiètrics en seqüències peptídiques es considera un enfocament útil per a millorar l'activitat biològica de pèptids. Tenint en compte la dificultat d'arilar la posició 4 (5) de l'anell d'imidazole, aquesta tesi doctoral es centra en el desenvolupament de noves estratègies eficients per a la preparació en fase sòlida d'undecapèptids antimicrobians contenint una 5-arilhistidina a través d'una reacció de Suzuki-Miyaura sota irradiació microones. L'extensió d'aquesta metodologia ha permès la síntesi de pèptids biarílics cíclics de diferents mides que incorporen un enllaç His-Phe 0 His-Tyr. Posteriorment, s'ha desenvolupat un procediment per la síntesi total en fase sòlida de lipopèptids biarílics cíclics derivats de les arilomicines. Les estratègies anteriors s'han estès a la preparació de compostos biarílics anàlegs dels pèptids bicíclics marins aciculitines. Concretament, s'ha preparat anàlegs dels hemisferis nord i sud de las aciculitines així com pèptids biarílics bicíclics que incorporen un pont Phe-Phe, Phe-Tyr, Tyr-His 0 Tyr-Tyr.
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Zerkout, Saïd. "Synthèse d'hydrazino peptides." Vandoeuvre-les-Nancy, INPL, 1994. http://www.theses.fr/1994INPL052N.
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La modification de la liaison amide dans les peptides a plusieurs conséquences potentielles: une biodégradabilité réduite, une possible modulation structurale due aux perturbations du réseau de liaisons hydrogène, et éventuellement, une bio-activité modulée pour l'analogue pseudopeptidique résultant, sans nécessiter de changer les chaines latérales. Nous avons étudie les perturbations structurales induites par la substitution d'une liaison amide par un groupe hydrazide dans diverses séquences mono-, di- et tripeptidiques protégées à leurs deux extrémités par une fonction amide, et contenant l'analogue hydrazine de la proline ou de l'alanine. L'analyse conformationnelle a été conduite à l'état solide par diffraction des rayons X, en solution par spectroscopie infrarouge et résonance magnétique nucléaire du proton, et par modélisation moléculaire. Après des considérations générales sur les structures des peptides et pseudopeptides, l'aspect chimique et technique de ce travail est présenté dans le second chapitre. Le troisième chapitre rassemble les données spectroscopiques et les conclusions sur les structures présentes qui sont ensuite discutées en référence aux séquences peptidiques originelles. La conclusion principale est que le groupe hydrazide induit localement un repliement du à la nucléophilie de l'oxygène du carbonyle et de l'azote alpha qui participent tous les deux a une liaison hydrogène bifide avec le site N-H amide immédiatement situe en aval. La conformation repliée qui en résulte est très stable, et capable de donner naissance à une forme globalement repliée de la molécule, de façon très semblable au repliement beta dans les peptides
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Groussier, Marianne Francoise Andree. "A new orthogonal protecting-group strategy for lanthionine-containing peptides." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325663.
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Pavlov, Nikola. "Synthèse asymétrique d’analogues de β2-tryptophane et application en synthèse peptidique". Thesis, Montpellier 2, 2011. http://www.theses.fr/2011MON20186/document.
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Le tryptophane est un acide aminé essentiel qui, en plus de son rôle dans la biosynthèse des protéines, est le précurseur biochimique de nombreux composés. Beaucoup de peptides biologiquement actifs, qui possèdent dans leurs séquences cet acide aminé contenant un substituant indole, ont des propriétés physiologiques importantes. On peut citer par exemple des dérivés comme la sérotonine, le tryptamine, le sumatriptan qui ont des effets neurophysiologiques. Les analogues de tryptophane sont aussi des « building block » important pour la synthèse de peptidomimétiques, d'analogues de produits naturels et de composés biologiquement actifs. Une autre propriété importante du tryptophane et de ses analogues concerne la fluorescence du noyau d`indole qui peut être utilisée par exemple pour l`étude de changements conformationnels d'une protéine et aussi l'étude des interactions protéine-membrane.Dans ce contexte, cette thèse est consacrée à la mise au point d'une nouvelle stratégie de synthèse asymétrique permettant d'accéder efficacement à d`analogues énantiopurs du tryptophane : les beta 2-tryptophanes (2-indolyl-beta-alanines) ainsi qu'à la synthèse et l'étude de nouveaux analogues de peptides à activité opioïdes contenant ces analogues. Nous avons développé une nouvelle stratégie de synthèse asymétrique permettant d'accéder efficacement à des analogues de beta 2-tryptophane (2-indolyl-beta-alanines) énantiopurs. - Nous avons effectué la synthèse d`un auxiliaire chiral le (R)-4-(3-hydroxy-4,4-diméthyl-2-oxopyrrolidin-1-yl) benzoate de benzyle ainsi que celle du dérivé nitroacrylate correspondant : le (R)-4-(3-(3-nitroacryloyloxy)-4,4-diméthyl-2-oxo pyrrolidin-1-yl) benzoate de benzyle ((R)-10). Les composés racémiques ont également été synthétisés pour préparer les témoins racémique des molécules cibles.- Nous avons mis au point des conditions optimisées de la réaction d`alkylation de Friedel-Crafts entre ce nitroacrylate chiral et divers indoles.- Nous avons également étudié pour chaque produit ainsi obtenu les meilleures conditions de transformation conduisant à la synthèse des analogues des N-Fmoc-beta 2-tryptophanes racémiques et optiquement purs.- Nous avons contrôlé l'absence d'épimérisation pouvant se produire pendant les réactions de transformation des produits optiquement purs et déterminé sans ambiguïté la configuration absolue des 2-indolyl-beta-alanines isolées.- Nous avons synthétisé sur support solide par stratégie-(Fmoc) 4 nouveaux peptides potentiellement biologiquement actifs et 2 peptides de référence - analogues raccourcis de la nociceptine<br>Tryptophan, an essential amino acid, both functions as a building block in protein biosynthesis and as a biochemical precursor. It is abundantly found in most biologically active peptides that exhibit various physiological properties in particular hormonal and antimicrobial activities. Some of its natural derivatives like serotonin, tryptamine, and also unnatural derivatives such as sumatriptan, have neurophysiologic effects. Tryptophan analogues are also important building blocks for the synthesis of peptidomimetics, natural products and biologically active compounds. Another important property of tryptophan and tryptophan analogues is related to the fluorescence of the indole ring that can be used to study conformational changes in protein and in protein-membrane interactions. The asymmetric Friedel-Crafts alkylation of various indoles with a chiral nitroacrylate provides optically active beta-tryptophan analogues after reduction of the nitro group and removal of the chiral auxiliary. This reaction generally occurs in good yield and high diastereoselectivity (up to 90:10). We have established a new route to prepare enantiopure beta-tryptophan analogues ((S)-2-indolyl-beta-alanines). We showed that beta-nitroacrylate (R)-2 is a good chiral auxiliary for asymmetric Friedel-Crafts alkylation of indoles. (R)-2-indolyl--alanines were obtained by the same synthetic route by using the chiral compound (S)-2. beta-tryptophan analogues are delivered in their N-Fmoc-protected form, ready to use for instance in solid phase peptide synthesis, which is one of the most popular method for peptide synthesis. This study provides a new example of asymmetric beta-tryptophan analogues preparation and further studies concerning their applications in medicinal chemistry and in organic synthesis are now in progress
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Pahlke, Denis. "Synthesis, characterisation and sensor-functionalisation of transmembrane β-peptides". Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://hdl.handle.net/21.11130/00-1735-0000-0003-C180-1.
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