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1
Jaulent, Agnes Marianne. "Design, synthesis and biological assay of peptidic protease inhibitors". Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416585.
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Rihakova, Lenka. "New peptidic angiotensin II analogues : their synthesis and pharmacological characterization". Thèse, Sherbrooke : Université de Sherbrooke, 2001. http://savoirs.usherbrooke.ca/handle/11143/4154.
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Sood, Geeta. "Base modified peptidic nucleic acids: synthesis and crystallographic analysis of intermediates". Thesis, Aston University, 1998. http://publications.aston.ac.uk/10967/.
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Peptidic Nucleic Acids (PNAs) are achiral, uncharged nucleic add mimetics, with a novel backbone composed of N-(2-aminoethyl)glycine units attached to the DNA bases through carboxymethylene linkers. With the aim of extending and improving upon the molecular recognition properties of PNAs, the aim of this work was to synthesjse PNA building block intermediates containing a series of substituted purine bases for subsequent use in automated PNA synthesis. Four purine bases: 2,6~diaminopurine (D), isoGuanine (isoG), xanthine (X) and hypoxanthine (H) were identified for incorporation into PNAs targeted to DNA, with the promise of increased hybrid stability over extended pH ranges together with improvements over the use of adenine (A) in duplex formation, and cytosine (C) in triplex formation. A reliable, high-yielding synthesis of the PNA backbone component N -('2- butyloxycarbonyl-aminoethyl)glycinate ethyl ester was establishecl. The precursor N~(2-butyloxycarbonyl)amino acetonitrile was crystallised and analysed by X-ray crystallography for the first time. An excellent refinement (R = 0.0276) was attained for this structure, allowing comparisons with known analogues. Although chemical synthesis of pure, fully-characterised PNA monomers was not achieved, chemical synthesis of PNA building blocks composed of diaminopurine, xanthine and hypoxanthine was completely successful. In parallel, a second objective of this work was to characterise and evaluate novel crystalline intermediates, which formed a new series of substituted purine bases, generated by attaching alkyl substituents at the N9 or N7 sites of purine bases. Crystallographic analysis was undertaken to probe the regiochemistry of isomers, and to reveal interesting structural features of the new series of similarly-substituted purine bases. The attainment of the versatile synthetic intermediate 2,6-dichloro~9- (carboxymethyl)purine ethyl ester, and its homologous regioisomers 6-chloro~9- (carboxymethyl)purine ethyl ester and 6-chloro-7-(carboxymethyl)purine ethyl ester, necessitated the use of X-ray crystallographic analysis for unambiguous structural assignment. Successful refinement of the disordered 2,6-diamino-9-(carboxymethyl) purine ethyl ester allowed comparison with the reported structure of the adenine analogue, ethyl adenin-9-yl acetate. Replacement of the chloro moieties with amino, azido and methoxy groups expanded the internal angles at their point of attachment to the purine ring. Crystallographic analysis played a pivotal role towards confirming the identity of the peralkylated hypoxanthine derivative diethyl 6-oxo-6,7-dihydro-3H-purlne~3,7~djacetate, where two ethyl side chains were found to attach at N3 and N7.
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Mulani, Amina. "Synthesis and Evaluation of Peptidic Probes for Tissue Transglutaminase and Factor XIIIa". Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31224.
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Transglutaminases (TGases) are a group of enzymes that catalyze the formation of an amide bond between the γ-carboxamide group of a glutamine residue and an amine donor, usually an ε-amino group of the lysine residue, leading to the formation of ε-(γ-glutamyl)lysine crosslinks. Owing to the roles that transglutaminases such as tissue transglutaminase (TG2) and Factor XIIIa (FXIIIa) have been found to play in a wide range of disease states, efforts have been directed towards the study of these proteins. The study of enzymes to better understand their function and mode of action is facilitated through the use of tools such as protein labelling, enzyme inhibition, and substrate analogue kinetic studies among others.
Transition state analogues have been effective inhibitors in the study of enzyme activity. Sulfoxide inhibitors can efficiently mimic transition states leading to the tetrahedral intermediate of an acyl transfer reaction and we discuss the synthesis towards sulfoxide transition state analogue inhibitors of TG2 in chapter 2. Novel sulfoxide compounds were synthesized, though the desired target compounds proved difficult to isolate due to their instability.
Fluorescent probes are effective in protein labelling as a means of discerning activity. This technique was applied in order to elucidate intracellular TG2 activity, which is a topic of controversy. To that end, the synthesis of a fluorescent, TG2-specific, cell permeable probe is discussed in chapter 3. However, preliminary in vivo results show that while the probe is cell permeable and fluorescent, it was not TG2-specific. Molecular modelling suggests that the hexa-arginine tag, designed to improve cell permeability, decreases the affinity of the probe for its intended target.
Finally, FXIIIa has become a new addition to the study of transglutaminases in the Keillor group. Given our interest in this enzyme, we had three goals for this work as explained in chapter 4. Firstly, owing to the anticipated high demand for FXIIIa required for later experiments, our primary aim was the development of an optimized method for the expression and purification of recombinant FXIIIA. After evaluating different conditions for FXIIIA expression, the Studier auto-induction ZYP media1 at 20 °C for 24 h was found to provide the optimal conditions for the expression of recombinant GST-tagged FXIIIA, typically giving a total of 1.5 mg of protein/L of culture.
Secondly, a variety of different peptides were synthesized and tested using a glutamate dehydrogenase (GDH)-based assay to identify a high affinity sequence for a substrate of FXIIIa. The two peptides with the highest affinity for FXIIIa were Ac-DQMMMAF-OH and Ac-DQMML-OH. Testing with TG2 displayed negligible reactivity, confirming their use as orthogonal peptides, results reinforced by modelling studies of the peptides with both FXIIIa and TG2. This discovery represents the first time peptides orthogonal to TG2 with affinity for FXIIIa have been kinetically characterized with both transglutaminase enzymes.
Lastly, our work towards a fluorogenic activity assay by incorporating a coumarin ester through attachment to a glutamic acid residue into a peptide sequence recognized by FXIIIa, will be discussed.
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Hernandez, Maria Luisa Escudero. "Enzymatic desymmetrization of prochiral cyclohexanones : synthesis of a non-peptidic NK2 antagonist". Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343757.
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Willems, Hendrika Maria Gerarda. "The design and synthesis of non-peptidic α-helix and β-turn mimetics". Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627463.
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Lamm, Matthew S. "Molecular self-assembly design, synthesis, and characterization of peptidic materials for bio- and nano-technologies /". Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 136 p, 2008. http://proquest.umi.com/pqdweb?did=1456296191&sid=2&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Remesic, Michael Vincent y Michael Vincent Remesic. "The Design, Synthesis, and Biological Evaluation of Novel Peptidic Ligands for the Treatment of Chronic Neuropathic Pain". Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/625593.
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Chronic neuropathic pain is a disease that impacts the livelihood of millions of people in the United States with no effective pain treatments and limited information pertaining to the underlying mechanisms. Opioid therapy is considered the gold standard for pain therapeutics, but chronic use of these medications brings about serious side effects such as tolerance, addiction, and respiratory depression which limit their overall therapeutic potential. Herein, two approaches are discussed to circumvent these issues: i) a multifunctional approach using N-phenyl-N-piperidin-4-yl-propionamide (Ppp) coupled to various endogenous opioid ligand scaffolds, and ii) non-opioid dynorphin A (DYN A) ligands at the Bradykinin-2 receptor (B2R).
The μ-opioid receptor (MOR) upon agonist stimulation provides analgesia and concomitant activation of the δ-opioid receptor (DOR) leads to an increased antinociceptive effect. Chronic activation of the MOR has been correlated with an upregulation of the κ-opioid receptor (KOR) and KOR associated side effects such as anxiety and depression. The discovery of a new class of opioid receptor (OR) ligands that have the biological profile of MOR/DOR agonists and KOR antagonists would be beneficial considering they would have an increased analgesic effect, leading to a lower dosage being administered and thus lower overall side effects, and block symptoms elicited from KOR stimulation. Discussed are various structure activity relationships (SARs) of numerous scaffolds that present novel biological profiles. Ultimately, we discovered a compound that, to our knowledge, is the 1st MOR/DOR agonist and KOR antagonist.
DYN A is the endogenous ligand for the KOR and its [des-Tyr1]-DYN A fragment interacts with the B2R, but not the KOR, promoting hyperalgesia. Peptidomimetic non-opioid DYN A analogues were synthesized and evaluated at the B2R. A minimum pharmacophore was identified and antagonists with both improved biological stability and affinity were discovered.
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Minta, Ewelina. "Synthesis and structure-activity relationship of peptidic analogues of omega-agatoxin IVB, pharmacological toll in cognition studies : towards calcium channel modulators". Montpellier 2, 2006. http://www.theses.fr/2006MON20072.
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Ce manuscript décrit la synthèse et l'évaluation biologique d'analogues de l'w-agatoxine IV B dans le but de trouver de nouveaux outils pour l'étude de l'activité de canaux calciques. L'w-agatoxine IV B est une neurotoxine peptidique isolée du venin d'araignée Agelenopsis aperta qui à ce jour est l'inhibiteur spécifique et sélectif des canaux calciques de type P (avec l'w-agatoxine IV A). Les canaux calciques de type P sont les canaux dépendant du voltage impliqués dans la neurotransmission dépendante du Glutamate dans le système nerveux central. La synthèse de structures peptidiques simplifiées, en comparaison avec celle de la toxine native, est décrite. L'étude du choix de la cible biologique, avec une approche modélisation moléculaire et la méthodologie de synthèse de differents analogues linéaires et cycliques de cette neurotoxine sont présentées. Les composes sont synthétisés par synthèse peptidique en phase solide (SPPS) en stratégie Fmoc avec une étude particulière sur les conditions de cyclisation et le choix de groupements protecteurs appropriés pour cette réaction de cyclisation. Les modifications des peptides naturels pour obtenir de nouveaux composés biologiquement actifs incluent les modifications des chaines latérales et l'insertion d'aminoacides non naturels (7-azatryptophane, D-Trp-OH, analogue phosphonique du Trp). Les peptides synthétisés ont été testés par des méthodes électrophysiologiques (patch Clamp); les activités biologiques des peptides linéaires et cycliques sont corrélées à l'aids d'analyses structurales par RMNThis dissertation concerns the synthesis and biological evaluation of w-agatoxin IV B mimetics in order to find a new tool for studying calcium channel's activity. W-Agatoxin IVB is one of the neurotoxins extracted from American funnel web spider Agelenopsis aperta, which is to date the only (along with w-agatoxin IVA) very selective gating inhibitor of the P-type calcium channels. Voltage-gated P-type Ca2+ channels are closely involved in glutamate-dependant neurotransmission in mammalian central nervous system (CNS). The syntheses of structurally simplified peptides, in comparison with native toxin, but still with retention of activity, are described. Then, the studies on choice of the biological target, including molecular modelling approach and the methodology of synthesis of different - linear and cyclic - analogues of w-AGA IVB are presented. The compounds were synthesized using solid phase peptide chemistry (SPPS) and Fmoc strategy, with particular consideration for the cyclisation conditions and the insight into selection of protective groups used for peptide cyclisation. Modifications of naturally occurring peptides in order to obtain biologically active components are taken into consideration, which include, among others, side chain modifications and non-natural amino acid insertion (7-AzaTrp, D-Trp, phosphonic analogue of tryptophan). The synthesized peptides were tested using neurophysiological techniques (patch clamp); the biological activity is correlated with NMR structures of cyclic and linear peptides
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Caporale, Andrea. "Function-structure relationship of PHT(1-11) analogues". Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425540.
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Parathyroid hormone (PTH) is an 84 amino acid peptide hormone produced in the parathyroid glands. It acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the 1-34 N-terminal fragment of PTH is sufficient to bind and activate the PTH type I receptor (PTH1R). The study of reduced-size PTH agonist and antagonist analogues has been the subject of extensive research for the development of bone anabolic drugs. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH1R showed that some modifications can increase signalling potency in peptides as short as 11 amino acid residues (e.g. S3→A3, N10→Q10, L11→R11).
This work of PhD thesis represents our effort to investigate the role of side chains and structural characteristics of N-terminal domain of PTH(1-11). We applied the hierarchical approach and some peptidomimetics concepts to synthesize specific libraries of peptide to obtain information about hormone/receptor interaction. With these information, we have been able to project a first example of peptidomimetic of PTH. The strategical role of Val2 in the interaction with the
PTH1R receptor was demonstrated and confirmed. We have observed that guanidine group in C-terminus has a specific role in the binding to the receptor for the shortest PTH(1-11) fragment. We have shown that substitutions with alpha-MeNle
at positions 8 can increase helix stability which can be also stabilized and promoted through a bridge between 6 and 10 positions. We synthesized a group of active analogues which are characterized by a stable alpha-helix in all peptide sequences and have the correct orientation of essential esidues 2, 5, 8 and 11.
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Zhou, Mingzhou. "Design and Combinatorial Synthesis Approach of Non-peptidic Trimeric Small Molecules Mimicking i, i + 4(3), i + 7 Positions of alpha-Helices". Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3456.
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Protein-protein interactions are key to several biological processes that facilitate signal transduction and many other processes. These interactions are involved in pathways that are critical to many human diseases. Targeting specific protein-protein interactions is a challenging goal because protein-protein interactions are predominately through hydrophobic interactions. Antagonists of the protein-protein interactions need to be perfectly fit into the binding pockets to ensure the activity. The -helical domain of the proteins behaves as the recognition motifs for numerous protein-protein, and protein-nucleic acid interactions. Research has shown that pathways of many diseases contain protein-protein interactions involving -helical domains, e.g. neurological disorders, bacterial infections, HIV and cancer, etc. It is difficult yet very important to design small molecules to target the shallow binding areas of protein-protein interactions. So far the most successful one is Hamilton’s 1,4-terphenylene scaffold, which has been used to target the interactions between p53/MDM2, Bak/Bcl-xL etc. Inspired by this, we designed and synthesized three new scaffolds of non-pepditic -helical mimetics, mimicking the i, i + 4, i + 7 positions of an -helix. There are three basic principles that were leading our design. The side chains of our designed molecules should act as mimetics of the side chains of an -helix. Second, our molecules should possess improved water solubility. Third, the molecules should be easy to synthesize to generate a focused library. Some of our molecules, including the ones whose molecular weight are as low as 294, started to show some inhibition against p53/MDM2 interactions.
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Fittler, Heiko [Verfasser], Harald [Akademischer Betreuer] Kolmar, Katja [Akademischer Betreuer] Schmitz, Gerd [Akademischer Betreuer] Buntkowsky y Markus [Akademischer Betreuer] Biesalski. "Peptidic inhibitors of therapeutically relevant proteases: Design, synthesis, and functional evaluation / Heiko Fittler. Betreuer: Harald Kolmar ; Katja Schmitz ; Gerd Buntkowsky ; Markus Biesalski". Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2015. http://d-nb.info/111214188X/34.
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Chen, Fei y 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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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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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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Lam, Hiu-yung y 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.published_or_final_version
Chemistry
Doctoral
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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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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Beena, T. K. "Antigenic Determinants Of Chicken Riboflavin Carrier Protein: Structural And Functional Aspects". Thesis, Indian Institute of Science, 1994. http://hdl.handle.net/2005/141.
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Investigations detailed in this thesis constitute a part of the continuing programme of research undertaken in our laboratory on the riboflavin carrier protein (RCP) with particular reference to identification and synthesis of neutralizing antigenic determinants, design of relevant epitope mimetics with improved immunogenic characteristics and relationship between their secondary structures and immunological properties.
The riboflavin carrier protein is elaborated as a reproductive stratagem to ensure adequate vitamin deposition in the developing oocyte in the chickens. The protein is scrupulously conserved through evolution in terms of physico chemical and immunological characteristics from fish through birds to mammals, including primates. In rodents and subhuman primates immunization with the heteroantigen viz., chicken egg white RCP leads to functional neutralization of the endogenous maternal protein resulting in curtailment of early pregnancy. Thus, the crucial role of RCP in maintenance of pregnancy is established and the protein identified as a potential candidate vaccine for immimocontraception. Further studies with the reduced and carboxymethylated (RCM) RCP as the immunogen reveal that antibodies induced by RCM-RCP are equally effective in bioneutralization of the endogenous protein. So it can be surmised that the native folded structure of RCP is not obligatory for eliciting bioneutralizing antibodies. In an attempt to identify functionally relevant regions of the protein, a panel of monoclonal antibodies (MAbs) have been raised and characterized. One of the MAbs viz., 6J32Ci2 could bring about early fetal resorp-tion when injected to mice with confirmed pregnancies. These results prompted a detail molecular immunological approach to understand underlying mechanisms. The principal aims of the present investigations include: (1) identification of neutralizing epitopes; (2) synthesis of peptidyl sequences incorporating these determinants; (3) an understanding of the structure, antigenic and immunogenic characteristics of these peptides; (4) correlation of conformational and antigenic characteristics; (5) rational design and synthesis of peptide analogs with greater propensity to assume predicted secondary structures; (6) analysis of conformation dependency of peptide antigens and the importance of such conformation in generating an optimal B-cell response; (7) the efficacy of the antibodies elicited by these Peptide antigens in neutralizing endogenous protein with the ultimate aim of designing synthetic vaccines.
Chapter 1 of this thesis deals with a general introduction summarizing the current status of knowledge regarding the chemistry and biology of RCP as well as synthetic peptides as potential immunogens. Chapter 2 outlines details of the experimental procedures adopted. Chapter 3 describes the results of investigations on the C-terminal fragment (residues 200-219) of cRCR The main consideration in selecting this sequence for the design of a potential peptide-based vaccine relied on the epitopic specificity of the neutralizing MAb 6S2C12. Epitope mapping using the Pepscan method revealed that the monoclonal antibody recognizes a core sequence corresponding to residues 203-210 of the cRCP. A 21-residue synthetic peptide (C-21) comprising this epitope was synthesized and antibodies elicited to the peptide conjugated to two different carriers, namely diphtheria toxoid and purified protein derivative (PPD) for T-cell help. In both active and passive immunoneutralization experiments, the peptide specific neutralizing antibodies interfered with the biological function of the protein and hence either protected from pregnancy or caused early fetal resorption in rodents as well as in sub-human primates. The conforma-tional properties of the peptide in aqueous buffers were analyzed from circular dichroism which revealed the absence of any ordered structure in the native C-21 peptide. Theoretical predictions of secondary structure suggested a propensity for an t*-helical structure for this fragment in the native protein. Therefore, influence of the helix-promoting solvent, vizM 2,2,2,trifluroethanol (TFE) on the C-21 peptide was investigated. Addition of TFE resulted in spectral changes with negative bands at 208 and 222 nm and a positive band at 190 rim which are typical of an a-helix.
To gain more information on the conformational characteristics of this peptide, it was considered worthwhile to stabilize the native peptide in an a-helical conformation based on simple rational design principles. Towards this end, four analogs of the parent peptide were synthesized and helix stabilization was sought to be achieved by introducing either salt bridges or back-bone conformational constraints such as by incorporating a-amino isobutyric acid at appropriate positions. In all the analogs, the core sequence, recognised by the neutralizing MAb 6B2C12 was maintained intact to ensure induction of antibodies capable of recognizing the native protein. CD spectral analysis of the analog peptides indicated that all the engineered peptides had varying degrees of enhanced helicities as compared to the parent peptide. The immunogenicity of each analog was studied by to the relevant peptide-diphtheria toxoid conjugates and analyzing their reactivities with the native protein by direct and competitive ELISA. The results revealed that these engineered conformational analogs axe highly immunogenic eliciting high titers of anti-protein antibodies. The relative affinities of these antibodies to bind cRCP were investigated. The antibodies to peptide analogs had higher affinities for the native protein and a positive correlation was found between the helical content of the peptide antigen in question and the relative affinity of corresponding antibody. The antibodies directed to all the peptide analogs could block the function of RCP resulting in early embryonic resorption when administered to pregnant mice. An interesting pattern of immunological cross-reactivity has been observed with the native and designed peptides. Antibodies raised to constrained helical analogs could bind the C-21 peptide which is structurally flexible. In contrast, the antibodies raised to the flexible native peptide antigen were inefficient in recognizing the structured peptides. The ability of all the peptide antibody to bind the native protein has been interpreted in terms of a conformationally flexible C-terminus region in cRCP.
Chapter 4 details investigations on a 21-residue peptide (N- 21) from the N-terminiis (4-24) of the protein. Selection of this peptidyl sequence relied on theoretical prediction of potential sequential determinants on RCP other than at C-terminus as well as on the outcome of immunoneutralisation experiments using antibodies to egg yolk RCP which lacks the relevant C-terminal determinants. The structure of this peptide in solution was analyzed by two dimensional NMR and CD. NMR experiments revealed the presence of two structured regions in the peptide. Diagnostic nuclear Overhauser effects characteristics of reverse turns or short frayed helical segments over residues 3-9 and 18-21 of the peptide were obtained. CD spectra showed the presence of a strong, negative band at 204 nm over a wide range of solvent conditions, a feature which has been interpreted in terms of a "polyproline Il-like" segment encompassing residues 11-16 which corresponds to an interesting (X-Pro)^ repeat in the N-21 sequence.
Specific antibodies were generated to this peptide as a conjugate with diphtheria toxoid. Administration of the antipeptide antibodies could neutralize the protein in vivo as demonstrated by early embryonic loss in pregnant mice. In limited experiments the antipeptide antibodies showed propensity to protect bonnet monkeys from pregnancy over a few consecutive ovulatory cycles when titres are maintained elevated by periodic boosting. To address the relationship between peptide structures and antigenicity, epitope mapping of this antipeptide antibodies as well- as the polyclonal antibodies to native RCP was undertaken using the Pepscan method. The results reveal that antigenic regions correspond well to conformationally well-defined elements of structure with the polyproline II-like segment being a common antigenic determinant on both the peptide and the native protein. These observations are suggestive of the involvement of both the N and C-terminal regions of RCP in terms of its binding to putative plasma membrane receptors.
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Grauer, Andreas. "Synthetic receptors for the differentiation of phosphorylated peptides and synthesis and use of tetrahydrofuran amino acids". kostenfrei, 2009. http://epub.uni-regensburg.de/13399/.
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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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Ganga, Ramu Vasanthakumar [Verfasser]. "Studies on Chemical Synthesis of Peptides: Efficient Synthetic Methods for β-Amino Acids, Azides, Amino Acid Hydroxamates and Esters : Methodologies in peptide synthesis / Vasanthakumar Ganga Ramu". München : GRIN Verlag, 2011. http://d-nb.info/119000478X/34.
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Kollappillil, Somakumar Krishnakumar. "Synthesis and analysis of puromycin analogues and amphiphilic peptidyl-RNA conjugates". Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10086.
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Une étude récente sur le transfert peptidique pH dépendant effectuée avec divers ARNt aminoacyles a révélé la dépendance au pH du transfert peptidique. L’instabilité hydrolytique rend impossible l’obtention de la valeur expérimentale du pKa de l’eau donné pour le groupement α-amino des esters 3'-aminoacyladenosine. Comme les analogues de la puromycine sont les analogues les plus proches du 3’-terminal des ARNt aminoacyles et qu’ils contiennent une liaison amide stable en position 3’, il est intéressant de déterminer la valeur du pKa du groupement α-amino de différents analogues de la puromycine mais aussi de corréler ces valeurs de pKa aux valeurs de pKa des groupements ARNt aminoacyles correspondants obtenues par le transfert peptidique pH dépendant. Le premier chapitre de la thèse se concentre sur la synthèse de différents analogues de la puromycine et sur la détermination de leur basicité par une analyse RMN pH dépendante. Ce chapitre discutera aussi la conformation intrinsèque des analogues de la puromycine mesurée par la pH dépendance de leur constante de couplage J1’-2’. Les synthèses d’analogues dinucléotidiques, d’un analogue xylo-puromycine et d’un analogue de désoxyxylopuromycine seront aussi décrites. Les conjugués peptidyl-ARN miment des fragments importants d’intermédiaires de la transduction. Ces analogues peuvent être utilisés comme outils expérimentaux pour comprendre l’évolution de la synthèse codée des peptides. L’innovation dans le concept de ‘négoce moleculaire’ entre les peptides, les oligonucléotides et les bicouches lipidiques, qui pourrait être à la base de l’évolution de la synthèse peptidique contrôlée par l’ARN, nous a poussé à synthétiser des conjugués peptidyl-ARN amphiphiliques et à étudier leurs interactions avec les bicouches lipidiques. Dans le deuxième chapitre les stratégies de synthèse sur support solide utilisant des analogues de puromycine comme élément constitutif seront discutéesA recent pH dependent peptidyl transfer assay in the ribosome with various aminoacyl tRNAs revealed the pH dependence of the peptidyl transfer. Hydrolytic instability makes impossible to obtain the experimental bulk water pKa data for the α-amino groups of 3'-aminoacyladenosine esters. Since puromycin analogues are the most similar analogues of the 3’-end of the aminoacyl tRNAs and they contain a stable amide bond in 3’-position, the determination of the pKa value of the α-amino groups of different puromycin analogues and correlation of these pKa values with those of α-amino groups of the corresponding aminoacyl tRNAs obtained by pH dependent peptidyl transfer deserves attention. Chapter 1 of the thesis focuses on the synthesis of different puromycin analogues and on the determination of their basicities by a pH dependent NMR analysis. This chapter also analyses the intrinsic conformations accessed by the puromycin analogues, as measured by the pH dependence of their J1’-2’ coupling constants. The synthesis of dinucleotide analogues, a xylo-puromycin analogue and a deoxyxylopuromycin analogue will also be described. Peptidyl-RNA conjugates mimic important fragments of natural intermediates of translation. These analogues can be used as an experimental tool to understand the evolution of the coded synthesis of peptides. The novelty in the concept of a ‘molecular deal’ between peptides, oligonucleotides and lipidic bilayers, which may be the basis for the evolution of RNA controlled peptide synthesis, prompted us to synthesize amphiphilic peptidyl-RNA conjugates and to study their interactions with lipidic bilayers. In chapter 2 the solid support synthetic strategies using puromycin analogues as the building blocks will be discussed
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Troalen, Frédéric. "Utilisation de la synthèse peptidique en immunochimie : application à l'étude de protéines présentant différents niveaux d'organisation structurale". Paris 5, 1989. http://www.theses.fr/1989PA05P618.
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Kilian, Gareth. "Development and testing of liposome encapsulated cyclic dipeptides". Thesis, Nelson Mandela Metropolitan University, 2011. http://hdl.handle.net/10948/1397.
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Cyclic dipeptides have been well characterized for their multitude of biological activities, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently been shown to possess significant anticancer activity against a range of cell lines, despite the limitations of these two molecules with respect to their physicochemical properties. Low Log P results in poor cell permeability which can often be problematic for drugs with intracellular mechanisms of action. It can also results in poor biodistribution, and theoretical Log P values for cyclo(His-Gly) and cyclo(His-Ala) were extremely low making them ideal candidates for inclusion into a nanoparticulate drug delivery system. The aim of this study was therefore to formulate and evaluate liposome-encapsulated cyclic dipeptides that increase the tumour-suppressive actions of the cyclic dipeptides, while showing a high degree of specificity for tumour cells. While liposomes are relatively simple to prepare, inter batch variation, low encapsulation and poor stability are often problematic in their production and this has lead to very few liposomal products on the market. This study aimed at using a comprehensive statistical methodology in optimizing liposome formulations encapsulating cyclo(His-Gly) and cyclo(His-Ala). Initial screening of potential factors was conducted using a 25-1 fractional factorial design. This design made use of two levels for each of the five factors and abbreviated the design to minimize runs. Although not much information is provided by these types of designs, the design was sufficient in identifying two critical factors that would be studies further in a more robust design. The two factors selected, based on the screening study, were cholesterol and stearylamine content. These two factors were then used in designing a response surface methodology (RSM) design making use of a central composite rotatable vii design (CCRD) at five levels (-1.5, -1, 0, 1, 1.5) for each factor in order to better understand the design space. Various factors influenced the measured responses of encapsulation efficiency, zeta potential, polydispersity index, cellular uptake and leakage, but most notable were the adverse effects of increasing stearylamine levels on encapsulations efficiency and cholesterol levels on leakage for both cyclo(His-Gly) and cyclo(His-Ala) liposomes. Optimized formulations were derived from the data and prepared. Fair correlation between the predicted and measured responses was obtained. The cytotoxic activity of the encapsulated cyclic dipeptides were assessed against HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol (PEG) grafted to the liposome surface in order to target folate receptors showed good benefit in significantly decreasing the IC50 values recorded in all cells lines tested, particularly low folate HeLa cells with the lowest IC50 being recorded as 0.0962 mM for folate targeted cyclo(His-Ala). The results therefore indicate that hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes. Key words: Liposomes, cyclo(His-Gly), cyclo(His-Ala), cyclic dipeptides, HeLa, MCF-7, folate receptors, factorial design, response surface methodology (RSM), central composite rotatable design (CCRD).
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Linser, Sebastian. "Development of new antimicrobial peptides based on the synthetic peptide NK-2". [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=982021631.
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Ieronymaki, Matthaia. "Immunological and Conformational characterization of synthetic peptide probes for autoimmune diseases". Thesis, Cergy-Pontoise, 2016. http://www.theses.fr/2016CERG0831/document.
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Les maladies auto-immunes sont des maladies chroniques et hétérogènes caractérisées par des réactions du système immunitaire acquis contre les propres tissus sains de l'organisme. Ces maladies affectent presque 5% de la population mondiale et en particulier les jeunes adultes. La complexité de leur spectre est énorme et même si leur étiologie est encore incertaine, il a été démontré que des facteurs génétiques et environnementaux sont impliqués dans le déclenchement du mécanisme pathologique. Cependant, il est nécessaire d'utiliser des outils diagnostiques et / ou pronostiques fiables pour le diagnostic précoce avant que des dommages cellulaires irréversibles ne se produisent et pour surveiller la progression de la maladie.De nombreuses études ont mis en évidence la présence de différents auto-anticorps dans le sérum de patients atteints de maladies auto-immunes. Les auto-anticorps qui sont spécifiques d’une maladie peuvent être utilisés en tant que biomarqueurs (BM) pour son diagnostic alors que les auto-anticorps qui diffèrent en fonction de l'état de la maladie peuvent être utilisés dans le suivi des patients. En fait, dans le cas de l'auto-immunité, un BM facilement détectable et fiable peut être représenté par le titre d'un auto-anticorps spécifique.Dans ce contexte, nous nous intéressons à deux maladies différentes, la sclérose en plaques (SEP) et la gammapathie monoclonale, en utilisant l'approche chimique inverse via le criblage de librairies de peptides par des sérums de patients.En particulier, l'importance des anticorps anti-myéline, et surtout, des anticorps anti-MOG (myéline oligodendrocyte glycoprotéine) est toujours l’objet de débats, soulignant la question très controversée d'un rôle pathogène putatif d'anticorps anti-MOG dans la SEP. Dans cette thèse, nous avons étudié le rôle de MOG comme auto-Ag putatif dans la SEP en utilisant le modèle expérimental d’encéphalomyélite auto-immune (EAE). Ainsi, afin d'évaluer la présence d'un mécanisme d’« epitope spreading » des cellules B, à savoir l'apparition d'une réponse dirigée vers des épitopes distincts de l'agent pathogène induisant la réponse immunitaire, nous avons synthétisé et testé en tant que sondes antigéniques cinq peptides synthétiques qui couvrent la séquence 1-117 de MOG.La seconde étude a porté sur la sélection d'un peptide mimant l'épitope minimal reconnu par l'anticorps monoclonal commercial anti- natural killer cell-1 humain (anti-HNK-1) en utilisant la résonance plasmonique de surface (SPR). L’épitope HNK-1 est considéré comme le déterminant antigénique de la glycoprotéine associée à la myéline (MAG), un composant quantitativement mineur des gaines de myéline. On observe que les patients atteints de troubles neurologiques auto-immuns, tels que la gammapathie monoclonale à IgM et la polyneuropathie démyélinisante, développent souvent des anticorps anti-MAG ciblant spécifiquement l’épitope HNK-1. Par conséquent, l'identification et la caractérisation de ces anticorps est pertinente. Le peptide choisi suite à notre étude pourrait ensuite être utilisé chez des patients atteints de troubles neurologiques pour le développement d'un outil de diagnostic fiable ou de surveillance de l'activité de la maladie par l'identification d'anticorps anti-HNK-1 dans le sérum des patientsAutoimmune diseases (ADs) refer to chronic and heterogeneous diseases with acquired immune system’s reactions against the body’s own healthy tissues. ADs affect more than 5% of the population worldwide and especially young adults. The complexity of their spectrum is enormous and even if their etiology is still unclear, it was demonstrated that both genetic and environmental factors are involved in triggering the pathological mechanism. Hence, a reliable diagnostic and/or prognostic tool for an early diagnosis of ADs before irreversible cellular damage occurs and for monitoring their progression is demanded.Numerous studies have revealed the presence of different autoantibodies (auto-Abs) in sera of patients suffering from ADs. Autoantibodies that are specific for a disease can be used as biomarkers (BMs) for its diagnosis while autoantibodies that differ depending on the disease state can be used in the follow up of the patients. Actually, in the case of autoimmunity, an easily detectable and reliable BM may be represented by the titer of a specific auto-Ab.In this context, we aimed to identify target(s) of the response for two different ADs, multiple sclerosis (MS) and monoclonal gammopathy, using the chemical reverse approach, which involves the screening of focused antigen (Ag) libraries with patients’ serum.In particular, the significance of anti-myelin antibodies, and especially, anti- Myelin Oligodendrocyte Glycoprotein (anti-MOG) antibodies is still matter of debate, underscoring the highly controversial issue of a putative pathogenetic role of anti-MOG antibodies in MS. In this thesis we investigated the role of MOG as putative auto-Ag in MS using the experimental autoimmune encephalomyelitis (EAE) model. Moreover, in order to assess the presence of a B-cell epitope spreading mechanism, i.e. the occurrence of a response directed toward epitopes distinct from the disease-inducing agent, we synthesized and tested as antigenic probes also five synthetic peptides covering the 1-117 sequence of MOG.The second issue focused on the selection of a peptide mimicking the minimal epitope recognized by the commercial available monoclonal antibody anti-human natural killer cell-1 (anti-HNK-1) using Surface Plasmon Resonance (SPR) technique. HNK-1 epitope, is considered as the antigenic determinant of myelin-associated glycoprotein (MAG), a quantitatively minor component of myelin sheaths. It is observed that patients affected by autoimmune neurological disorders, such as IgM monoclonal gammopathy and demyelinating polyneuropathy, often develop anti-MAG antibodies specifically targeting the HNK-1 epitope. Accordingly, identification and characterisation of these antibodies is relevant. The selected peptide could be subsequently used in earlier stage patients for the development of a novel and reliable diagnostic tool for anti-HNK-1 antibody identification in sera of patients affected by autoimmune neurological disorders monitoring disease activity
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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.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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Dowden, James. "Synthetic receptors for peptidic guests". Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243928.
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Voss, Emelyne. "Synthèse d’Analogues Bis-azotés de la Proline et Applications". Thesis, Vandoeuvre-les-Nancy, INPL, 2011. http://www.theses.fr/2011INPL059N/document.
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La liaison peptidique au sein d’un peptide ou d’une protéine est d’ordinaire plane et en conformation trans pour la majorité des acides aminés. La situation est un peu différente en amont d’une proline : la barrière thermodynamique qui s’oppose à la rotation de la liaison amide est plus faible et la tendance de la liaison à rester plane est un peu moins grande. Cette liaison AA-Pro peut donc adopter une conformation cis, entraînant la formation d’un coude prononcé dans une chaîne peptidique à son niveau. Ce travail décrit la synthèse et la réactivité chimique de nouveaux analogues bis-azotés de la proline en solution permettant de favoriser la conformation cis d’une liaison AA-ΨPro. L’impact conformationnel que peut engendrer ces résidus au sein de pseudopeptides est également exposé. Dans un premier temps, une nouvelle voie d’accès à la α-azaproline énantiomériquement pure et orthogonalement protégée a été mise au point en exploitant des travaux antérieurs concernant la synthèse d’α-hydrazinoesters et de N-aminodipeptides. L’étude de la réactivité de cette pseudoproline a permis de définir les meilleures conditions de formations de pseudotripeptides de formule P1-AA1-δ-azaPro-AA3-P3. Elle a également orienté les travaux, dans un second temps, vers la synthèse de pseudopeptides incorporant un motif acide pyrazolique. Enfin, la structure des composés préparés a été analysée par RMN, IR et par modélisation moléculaire. L’examen des P1-AA1-δ-azaPro(Boc)-AA3-P3 a révélé la formation par liaison hydrogène d’un pseudocycle en C7, favorisant la conformation trans de la liaison AA1-δ-azaPro, alors que l’absence de la fonction Boc favorise la conformation cis de cette liaisonThe peptidic bond in a peptide or a protein is usually flat and in trans conformation for the majority of amino acids. The situation is a little bit different upstream the proline: the thermodynamic barrier which opposes the rotation of the amide bond is weaker and the tendency of the bond to remain flat is lesser. So, this AA-Pro bond can adopt a cis conformation, leading to the formation of a turn in the peptidic chain. This work describes the synthesis and the chemical reactivity of new bis-nitrogen analogous of proline in solution to facilitate the cis conformation of a AA-PΨPro bond. The conformational impact that these residues may generate in pseudopeptides is also exposed.Initially, a new access road to the orthogonally protected and enantiomerically pure δ-azaproline has been developed by exploiting previous work on the synthesis of α- hydrazinoesters and N-aminodipeptides. The study of the reactivity of this pseudoproline helped define the best conditions for forming pseudotripeptides of formula P1-AA1--δ-azaPro-AA3-P3. It also guided the work, in a second step, towards the synthesis of pseudopeptide incorporating a pyrazole acid motif. Finally, the structure of the prepared compounds was analyzed by NMR, IR and molecular modeling. Examination of the P1-AA1-δ-azaPro(Boc)-AA3-P3 revealed the formation of a pseudocycle C7 by a Hydrogen bond, favoring the trans conformation of the AA1-δ-azaPro bond, while the absence of Boc function seems to favor the cis conformation of this bond
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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."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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Seisel, Quentin. "Développement et vectorisation de peptides inhibiteurs du domaine PDZ de CAL pour le traitement de la mucoviscidose". Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT010/document.
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La mucoviscidose est une maladie génétique létale induite par des mutations du canal ionique CFTR, provoquant une perte de sa fonctionnalité au niveau des tissus épithéliaux de divers organes. Le poumon est particulièrement touché et devient sujet à des infections bactériennes chroniques. Dans le but de traiter la maladie, nous avons développé des « stabilisateurs » de la protéine CFTR : il s’agit de peptides inhibant l’interaction de la protéine CFTR avec le médiateur-clé de sa demi-vie à la membrane apicale des cellules épithéliales, la protéine CAL. En particulier, le peptide iCAL36 a démontré une hausse de fonctionnalité de la protéine CFTR mutée. Le but de cette thèse a été de renforcer cet effet biologique en améliorant ses caractéristiques pharmacologiques : pénétration cellulaire (vectorisation), stabilité métabolique et affinité pour la protéine CAL.Le premier axe d’optimisation a été l’internalisation du peptide iCAL36 par 7 différents peptides vecteurs (CPP). Les conjugués correspondants ont été évalués suivant leur cytotoxicité, leur efficacité d’internalisation et leur capacité à maintenir cette efficacité en présence de sérum. Le mécanisme d’entrée des deux meilleurs conjugués a ensuite été étudié. Divers biais couramment rencontrés lors de l’analyse de l’efficacité d’internalisation de peptides vecteurs par des méthodes de fluorescence ont également été identifiés et expliqués. La séquence du peptide iCAL36 a ensuite été modulée par inclusion d’acides aminés non-naturels. Le criblage des interactions peptide/protéine a été réalisé par une procédure optimisée dans le cadre de cette thèse (méthode PIPEPLUS) et a permis d’identifier 32 analogues prometteurs de la séquence d’iCAL36 incluant différentes substitutions. En particulier, une des séquences identifiées (iCAL-Q27) a démontré une affinité 70 fois supérieure à celle du peptide iCAL36 pour la protéine CAL, indiquant une inhibition plus complète de l’interaction CAL/CFTR.Ces résultats majeurs permettent dans leur ensemble de développer des « stabilisateurs » peptidiques de seconde génération pouvant avoir un effet biologique accru dans le contexte de la mucoviscidoseCystic fibrosis is a lethal disease induced by genetic mutations of the CFTR chloride channel, leading to a loss of its function in the epithelial tissues of various organs. The lung is particularly affected and becomes a target for chronical bacterial infections. To cure the disease, we developed so-called CFTR “stabilizers”, which are peptides inhibiting the interaction between the CFTR protein and the key mediator of its half-life at the apical membrane of epithelial cells, the CAL protein. In particular, the iCAL36 peptide showed an increase of the functionality of the mutated CFTR protein. The aim of this thesis was to increase this biological effect by improving its pharmacological parameters: cellular internalization (vectorization), metabolic stability and affinity for the CAL protein.The first axis of optimization was the internalization of the iCAL36 peptide by 7 different cell-penetrating peptides (CPP). The corresponding conjugates were evaluated upon their cytotoxicity, their uptake efficiency and their capacity to maintain this efficiency in the presence of proteases. The mechanism of entry of the two best candidates was then studied. Various bias frequently encountered during the analysis of CPP uptake efficiency by fluorescence methods were also identified and explained. Afterwards, the iCAL36 sequence was modulated by inclusion of non-natural amino acids. The screening of the peptide/protein interactions was performed by a method optimized during this thesis (PIPEPLUS process) and allowed the identification of 32 promising analogues of the iCAL36 sequence including several substitutions. In particular, one of these sequences (iCAL-Q27) showed an affinity 70 times stronger for the CAL protein compared to iCAL36, hinting a more complete inhibition of the CAL/CFTR interaction.Overall, these major results grant the access to second-generation “stabilizers” potentially showing an improved biological effect in the context of cystic fibrosis
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Liu, Yong-Peng. "Total Synthesis of Microsclerodermin D". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASF024.
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La microsclerodermine D est un peptide macrocyclique d’origine marine qui comporte six amino acides, dont deux sont disponibles commercialement : la glycine (Gly) et la sarcosine (Sar). Les quatre autres amino acides : l’acide (R)-γ-amino-β-hydroxybutyrique (GABOB), le D-6-chlorotryptophane (6-Cl-Trp), un β-amino acide polyhydroxylé (APTO) et l’acide 3-amino-4-hydroxypyrrolidinoacetique (PyrrAA) seront préparés via de nouvelles voies de synthèse. Notre objectif est de développer une voie de synthèse de la microsclerodermine D modulable et qui permettrait la synthèse d’autres membres de la famille des microsclerodermines et d’analogues. Nos nous intéresserons également à de potentielles études permettant d’évaluer leurs propriétés biologiques et leur potentiel en tant qu’agent anticancéreuxMicrosclerodermin D is a macrocyclic peptide of marine origin which contains six amino acids, of which two are commercially available: glycine (Gly) and sarcosine (Sar). The four other amino acids: (R)-γ-amino-β-hydroxybutyric acid (GABOB), D-6-chlorotryptophan (6-Cl-Trp), a polyhydroxylated β-amino acid (APTO) and 3-amino-4-hydroxypyrrolidinoacetic acid (PyrrAA) will be accessible by new synthetic routes. Our goal is to develop a modular synthetic route to microsclerodermin D that could be applicable for the preparation of other microsclerodermin family members and analogues thereof. We are also looking forward to make some investigations on their biological activities or potential as anticancer drug
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Inokuchi, Eriko. "Synthetic Studies on Peptide Bond Isosteres and Their Application to Biologically Active Peptides". 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142486.
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Das, Sanjit. "Methodological development in peptide chemistry for synthesis of antimicrobial and antifungal derivatives of marine natural peptides". Thesis, Perpignan, 2018. http://www.theses.fr/2018PERP0054.
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La chimie de clic est devenue indispensable dans les nombreux domaines de chimie associée à la conception de médicament. Dans ce contexte, comme nous savons(connaissons) l'étude concernant l'impact d'insertion triazole sur la conformation de peptaibol est limitée, nous avons conduit l'étude pour examiner l'impact et l'adaptabilité de 1, 1 4-disubstituted, 2, l'insertion 3-triazole dans peptaibols différent. Selon le résultat de cette expérience touchant à l'activité réduite et la conformation perturbée de l'analogue peptaibol, le substitut dipeptide décoré du fragment triazole portant substituents hydrophobe divers a été inséré à très N-ter la partie du peptaibol. L'amélioration du bioactivity et de la restauration de la conformation pour les analogues peptaibol a été observée et le fait a été aussi soutenu par les résultats obtenus de l'étude biophysique des analogues choisis d'ALM F50/5. Nous avons plus loin prolongé notre étude pour employer notre stratégie à être appliqué sur le peptide P42 thérapeutique qui souffre de la limitation de manque de perméabilité et de stabilité. Le peptide P42 est impliqué dans le pathophysiology de la maladie d'Huntington neurodégénératif. Un total de 12 analogues de peptide de P42-camelote a été synthétisé par SPPS par notre protocole optimize. Dans la deuxième partie, nous avons développé une stratégie pour synthétiser lipopeptide cyclique produit de l'espèce cynaobacterial marine. Notre objectif principal était de synthétiser Hormothamnin A, undecapeptide cyclique consistant de plusieurs acides aminés artificiels incluant dehydroamino acide (Dhaa) qui fait la synthèse de ce peptide compliqué. En raison de cette raison, premièrement, nous avons voulu appliquer notre stratégie de synthétiser Trichormamide A, une sorte relativement plus simple de cylic lipopeptide. Après l'accomplissement de cette tâche, une première tentative a été faite pour synthétiser Hormothamnin A. Le résultat préliminaire de ceci est présenté dans cette section. Enfin, nous avons essayé de développer une méthodologie robuste pour synthétiser Fmoc-Dhaa dans la phase de solution et son insertion dans l'ordre peptaibol par une norme(un standard) SPPS le protocole. Les résultats préliminaires que nous avons concernant la synthèse Dhaa et son insertion dans peptaibol sont aussi discutés ici de plus avec la synthèse de phase solide de Bergofungin naturel DThe click chemistry has become indispensible in the many areas of chemistry associated with drug design. In this context, as we know the study concerning the impact of triazole insertion on the conformation of peptaibol is limited, we have conducted the study to investigate the impact and adaptability of the 1, 4-disubstituted 1, 2, 3-triazole insertion into different peptaibols. Depending on the outcome of this experiment relating to reduced activity and perturbed conformation of the peptaibol analogue, the dipeptide surrogate decorated with the triazole moiety bearing various hydrophobic substituents was inserted at the very N-ter part of the peptaibol. The improvement of the bioactivity and restoration of the conformation for the peptaibol analogues was observed and the fact was also supported by the results obtained from the biophysical study of the selected analogues of ALM F50/5. We have further extended our study to employ our strategy to be applied on the therapeutic P42 peptide which suffers from the limitation of lack of permeability and stability. P42 peptide is involved in the pathophysiology of neurodegenerative Huntington’s disease. A total of 12 analogues of P42-TAT peptide were synthesized through SPPS by our optimized protocol. In the second part, we have developed a strategy for synthesizing the cyclic lipopeptide originated from marine cynaobacterial species. Our main objective was to synthesize Hormothamnin A, a cyclic undecapeptide consisting of several unnatural amino acids including dehydroamino acid (Dhaa) which makes the synthesis of this peptide complicated. Due to this reason, firstly, we have chosen to apply our strategy to synthesize Trichormamide A, a relatively simpler kind of cylic lipopeptide. After accomplishing this task, a first attempt was made to synthesize Hormothamnin A. The preliminary result of this is presented in this section. At last, we have tried to develop a robust methodology to synthesize Fmoc-Dhaa in solution phase and its insertion into the peptaibol sequence through a standard SPPS protocol. The preliminary results we have got concerning the Dhaa synthesis and its insertion into peptaibol are also discussed here in addition with the solid phase synthesis of natural Bergofungin D
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Schöwe, Markus Julian [Verfasser]. "Thioacid-Containing Peptides for the Convergent Synthesis of N-Glycopeptides and Peptide Conjugates / Markus Julian Schöwe". Konstanz : KOPS Universität Konstanz, 2019. http://d-nb.info/1234912279/34.
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Borrelli, Alexander P. "Synthetic Genes for Antimicrobial Peptides". Digital WPI, 2003. https://digitalcommons.wpi.edu/etd-theses/427.
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The goal of this project was to clone and express the antimicrobial peptide protegrin 1 (PG-1). Initially a yeast system was chosen but was discarded due to technical difficulties. Invitrogen's bacterial T7 expression system was chosen next to express the peptide. PG-1 expression was verified by anti-his immunoblot and then the peptide was purified by IMAC. Its activity was verified using a Bacillus subtillis radial diffusion assay.
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Harding, Simon J. "Studies in peptide synthesis". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363762.
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Hulme, Christopher. "Synthesis of peptide analogues". Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306621.
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Adamson, R. "Solid phase peptide synthesis". Thesis, University of Bradford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371460.
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Mijalis, Alexander James. "Automated flow peptide synthesis". Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/118272.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2018.Cataloged from PDF version of thesis.
Includes bibliographical references.
Though reported by Merrifield nearly sixty years ago, batch solid phase peptide synthesis remains slow at minutes to hours per residue. Here we report a fully automated, flow based approach to solid phase polypeptide synthesis with amide bond formation in seven seconds and total synthesis times of forty seconds per amino acid residue. Crude peptide purities and isolated yields were comparable to standard batch solid phase peptide synthesis. Process monitoring with absorbance spectroscopy allows for the immediate detection and rapid optimization of difficult-to-synthesize peptides. This instrument is flexible and allows for synthesis of peptide nucleic acids, glycopeptides, removal of orthogonal amine protecting groups, and click chemistry on the solid phase. At full capacity, this approach to peptide synthesis can yield tens of thousands of individual 30-mer peptides per year.
by Alexander James Mijalis.
Ph. D.
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Raphy, Gilles. "Solid phase peptide synthesis". Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/14254.
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A new method of purification has been developed for peptides synthesised by the Merrifield solid phase methodology. NPROB*LEM-17-Tetrabenzo(a,c,g,i)fluorenylmethoxycarbonyl glycine (Tbfmoc Gly OH) has been prepared, and coupled via its symmetrical anhydride or its HOBt ester to the N-terminus of a peptide at the final stage of the synthesis. The strong affinity of the Tbfmoc group for graphitised carbon (PGC) allows the retention of Tbfmoc-protected peptides on a column packed with this material, whilst incorrectly terminated sequences and other materials are washed away. Following deprotection of the Tbfmoc group under basic conditions, the free peptide can be eluted from the column. This method has been exemplified by the purification of Ubiquitin (53-76) OH and Ubiquitin (35-76) OH. Preliminary results indicate that the technique may be developed into a form of affinity purification suitable for the resolution of racemates using ligand-exchange chromatography (LEC).
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Sage, Matthew Arthur. "Synthesis of peptide mimetics". Thesis, University of Bath, 1995. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261380.
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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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Thomas, David William. "Studies in peptide chemistry". Thesis, University of Oxford, 1988. http://ora.ox.ac.uk/objects/uuid:8cf7679d-1a0b-4163-b9dd-87363c9bf806.
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The thesis discusses the design of potential inhibitors of Angiotensin Converting Enzyme (ACE). The synthesis of pep tide inhibitors containing arginine and histidine-type residues is described. Successful incorporation of these residues during peptide synthesis requires the use of protecting groups on the side-chains* and new developments in this area are described. Ch. 1 reviews the currently available protecting groups for histidine. A methodology for regiospecific introduction of protecting groups of type ROCH2-, via their corresponding chloromethyl ethers, is described. A convenient synthesis of these reagents (specifically t-Butoxymethylchloride, Dum-Cl and 2,4,6-TrimethyIbenzyloxymethyl- chloride, Tom-Cl) is given. Ch. 2 demonstrates that a knowledge of the location of histidine protecting groups has become mandatory, both in peptide synthesis and elsewhere. Two methods) a), nuclear Overhauser enhancement measurements and b), a procedure involving methylation, deprotection and amino-acid analysis are presented, which have allowed the differentiation of ? and ? derivatised histidines. Ch. 3 reviews the currently available protecting groups for arginine. Using 2-phenylethyIguanidine as a model for arginine, a number of haloacylguanidines and 5,5-disubstituted pyrimidinones wBe synthesised, and this chapter describes their structures, and the potential use of the corresponding reagents in protecting arginine during peptide synthesis. Ch. 4 describes the synthesis of his tidyIphenylalanylarginine and several variants on this structure. Biological data showing the level of inhibition both of A.C-E- and of Renal ^ndopeptidase by these compounds is presented. The syntheses also provide a further demonstration of the efficacy of the recently introduced benzyloxymethyI, (Bom)protecting group.
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Ward, G. J. "Imidazolines in peptide chemistry". Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381082.
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Pilkington-Miksa, Michael. "The synthesis of modified integrin-targeting peptides for incorporation into lipid/integrin-targeting peptide/DNA transfection complexes". Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445789/.
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Integrin-targeting peptides have been shown to increase transfection efficiency when included in a number of different non-viral vectors. In the case of Lipofectin/DN A complexes (LD), transfection efficiency has been shown to increase on incorporation of an integrin- targeting peptide (Lipid/Integrin-targeting peptide/DNA complexes), as seen by a 100-fold increase in luciferase expression. Efforts to improve the Lipofectin component of Lipid/Integrin-targeting peptide/DNA complexes continue to be made and consequently ways of increasing transfection efficiency through modifications to the integrin-binding peptide are also been investigated. The integrin- targeting peptide component of Lipid/Integrin-targeting peptide/DNA complexes investigated by Hart et al. has effectively three functionalities a 'head' which is complimentary to a specific integrin, a 'tail' which can bind to and condense DNA and a 'spacer' which links the 'head' and 'tail'. Both alternative spacers and DNA-binding motifs have been synthesised and incorporated into integrin-targeting peptides with the intention of investigating the effects of these modifications on the transfection efficiency as well as physical properties of Lipid/Integrin-targeting peptide/DNA complexes. In this thesis are reported the structures of unnatural amino acids synthesised and incorporated into integrin-targeting peptides, as well as some of the transfection results obtained.
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Kellam, Barrie. "The development of novel solid phase methodologies for the synthesis of atypical peptides and non-peptide entities". Thesis, University of Nottingham, 1996. http://eprints.nottingham.ac.uk/10381/.
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Solid phase peptide synthesis (SPPS) of branched/cyclic peptides, multiple antigenic peptides (MAPs), pseudopeptide toxins etc. requires amine protection orthogonal to the established Fmoc/Boc protocols. It was envisaged that progression from Dde to N-1-(4-Nitro-l,3-dioxoindan-2-ylidene)ethyl (Nde) amino acid protection would maintain the stipulated orthogonality, whilst improving the hydrazine mediated deprotection. A selection of Nα-Nde-amino acids were efficiently synthesised and their compatibility with SPPS conditions demonstrated by the synthesis of a number of peptides. The Nde group displayed a faster and more easily monitored deprotection profile and similar orthogonality when compared with the Dde group. The selective primary amine protecting characteristics of the Nde group was illustrated by the synthesis of N¹N⁸-bis Nde-spermidine which was subsequently utilised in the solid phase synthesis of the natural product, dihydrotrypanothione. Large peptides synthesised by SPPS often demand elaborate, expensive and cumbersome purification protocols. Dde based reversible amine protecting groups incorporating hydrophobic and affinity probes have been developed. Their ease of preparation and efficacy in the purification of synthetic peptides has been demonstrated. Intercellular communication in various Gram-negative microorganisms is often mediated by small signalling molecules, e.g. N-(3-oxohexanoyl)-L-homoserine lactone (OHHL). Detection of these molecules is often extremely difficult. To address this, SPPS procedures have been employed to couple N-β-ketoacyl-L-homoserine lactone containing haptens to a dendritic lysine scaffolding, and the resultant macromolecule evaluated for its ability to raise anti-N-β-ketoacyl-L-homoserine lactone antibodies. 1-Carbapen-2-em-3-carboxylic acid is a broad spectrum antibiotic produced by the Gram-negative Erwinia and Serratia microorganisms. Some key intermediates for the putative synthetic precursors have been successfully prepared in order to study the biosynthetic pathways by feeding blocke mutants of the above bacteria, and also to transpose the methodologies to a solid phase to construct carbapenem libraries. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.