Dissertations / Theses on the topic 'Peptidomimetic inhibitors'
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Appiah, Kubi George. "Development of Peptidomimetic Inhibitors Against Intracellular Targets." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587519549871245.
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Hirsch, Brett M. "Mechanism-Based Peptidic and Peptidomimetic Human Sirtuin Inhibitors." University of Akron / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=akron1302055499.
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Allwood, Daniel Martin. "Discovery and development of novel non-peptidomimetic inhibitors of XIAP." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607657.
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Vicari, Daniele. "Evaluation Of VEGF Peptide Mimics As Inhibitors Of Angiogenesis." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1221509932.
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Breuer, Christian [Verfasser]. "Design and Synthesis of Covalent Peptidomimetic Inhibitors for Human Cysteine Cathepsins / Christian Breuer." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1227990499/34.
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Watkins, Andrew M. "An in silico pipeline for the design of peptidomimetic protein-protein interaction inhibitors." Thesis, New York University, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10188557.
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Protein-protein interactions have historically been branded “undruggable” due to their intrinsic challenges above and beyond protein-small molecule interactions. Incrementally, system after system has been approached by a variety of specialized design strategies. Still, the vast majority of interactions are intractable, and the profusion of individualized strategies leave few general approaches that might be able to extend to recalcitrant systems.
The ecosystem of tools available for developing inhibitors of protein-protein interactions suggests a potential modular strategy for proceeding from protein structure to plausible interaction inhibitors. My dissertation describes an analysis of all the protein-protein interactions containing key interfacial structural motifs found in protein structures catalogued by the Protein Data Bank. This work provides both data on extant protein interactions and specific conclusions regarding directions for further peptidomimetic design. We describe the incorporation of our lab’s peptidomimetic scaffolds into Rosetta and the validation of those methods against valuable biological systems. Finally, I chronicle substantial extension to Rosetta’s capacity to accurately model and design peptidomimetic structures.
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Nurbo, Johanna. "Peptidomimetic Enzyme Inhibitors Targeting M. tuberculosis Ribonucleotide Reductase and Hepatitis C Virus NS3 Protease /." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-112345.
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Knuhtsen, Astrid. "Searching for inhibitors of the protein arginine methyl transferases : synthesis and characterisation of peptidomimetic ligands." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57228.
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Within the last two decades research in the field of epigenetics has increased significantly as targeting the epigenetic enzymes has the potential to alter the transcription of genes. Aberrant regulation of transcription is seen in several disease states, and drugs targeting the epigenetic histone deacetylases and DNA methylases are already marketed for cancer treatment. The Protein Arginine Methyl Transferases (PRMTs) belong to an epigenetic enzyme family that is upregulated in several cancers. However, currently no inhibitors of the PRMTs have been marketed. In this thesis several peptidomimetic strategies were utilised to modify the tryptophan residues in two peptide leads in order to discover new inhibitors of the PRMTs. One of these strategies involved constraining the side chain indole of tryptophan to the peptide backbone, thus producing a seven membered azepinone mimetic, Aia. The peptidomimetic efforts resulted in a structure-activity relationship study from which a constrained peptidomimetic containing two Aias was discovered to be a low micromolar inhibitor of several PRMTs. To characterise the inhibitor the conformation of the inhibitor was examined using solution-phase NMR and was shown to display an interesting turn-structure. The original peptide lead was fluorescently tagged and investigated in a cellular setting, but did not reveal any PRMT-specific localisation.
In an effort to study the binding of the discovered inhibitor with the PRMTs, protein expression in E. coli and purification was performed. This resulted in the optimisation of PRMT6 purification in order to obtain highly pure PRMT6 for isothermal titration calorimetry (ITC) studies. Unfortunately these ITC studies were unsuccessful.
Furthermore, as the constrained tryptophan mimetic had proven very useful in the peptidomimetic inhibitors of the PRMTs, we attempted to synthesise a lysine/arginine dipeptide mimetic using aziridine chemistry.Pharmaceutical Sciences, Faculty of
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Kamath, Jayesh Ramrao. "Development of pseudosubstrate-based peptide and peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ protein tyrosine kinase using combinatorial chemistry technology." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289173.
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Several protein tyrosine kinases and the signaling pathways in which they participate have emerged as attractive targets for drug design. Specific and potent PTK inhibitors not only represent a new class of anticancer agents but may also be used as a powerful research tool to study the role of PTK-dependent cellular pathways in normal or tumor cell growth and to dissect the redundancy in signal transduction pathways. Dr. Lam's laboratory has previously reported identification of efficient and specific peptide substrates for p60ᶜ⁻ˢʳᶜ PTK using one-bead one-peptide combinatorial library method (Lam et al., 1995; Lou et al., 1996a and b). Based on the structure of these peptide substrates, I have identified and characterized potent and selective peptide inhibitors of p60ᶜ⁻ˢʳᶜ PTK. Some of the identified peptide inhibitors were used as a research tool in this dissertation to investigate the active site of the enzyme p60ᶜ⁻ˢʳᶜ PTK. In addition to potency and selectivity, a major criterion for a successful src inhibitor is its cell permeability as src is located inside the cell. Peptides are generally impermeable to cell membrane. A major accomplishment of this dissertation is development of cell permeable peptidomimetic inhibitors of p60ᶜ⁻ˢʳᶜ PTK based on the identified dipeptide motif --Ile-Tyr- (-I-Y-). This dissertation describes identification of tetrameric and trimeric peptidomimetic inhibitors using a combination of two combinatorial methods, the 'one-bead one-compound' combinatorial method and the 'iterative' combinatorial method. Some of the identified inhibitors seem to selectively affect transformed cells versus normal cells at lower concentrations. A lot of still needs to be done to optimize these inhibitors. However, the accomplished work in this dissertation proves the feasibility of the pseudosubstrate peptide-based approach for the development of cell permeable peptidomimetic inhibitors as anti-cancer therapeutic agents.
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Doligalski, Michael Lawrence. "Design and Development of Peptidomimetic Ligands for Targeting Radiopharmaceuticals, Imaging Probes, and Immunotherapeutics in Oncologic Disease." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6492.
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Cancer is a leading cause of morbidity and mortality in the developed world. While much has been learned about these diseases in the last few decades, one of the main barriers to widespread advancement is the heterogeneity of cancer biology. A growing body of evidence supports the idea that certain protein receptors are overexpressed on the surface of tumor cells as compared to normal tissues. These extracellular biomarkers provide a unique opportunity to selectively target the tumor with both imaging and therapeutic modalities. The research in this dissertation focuses on targeting proteins on the tumor cell surface with peptidomimetic ligands.
Following a description of various extracellular receptors, chapter one discusses targeting ligands designed to specifically and selectively bind these receptors. It reviews recent literature on targeted alpha-particle therapy and ends with an explanation of the advantages of peptide ligands. Three distinct approaches to imaging and therapeutic modalities are then discussed in subsequent chapters. First, a peptide ligand was designed to target radionuclides to malignant melanoma cells in an effort to develop companion radiotherapeutics and diagnostic imaging agents. The second research project describes the synthesis of a novel antagonist peptide ligand with conjugated near infrared dye, and its utility for real-time intraoperative guidance during pancreatic adenocarcinoma resection. Finally, the last chapter describes how the relatively new field of immunomodulatory effectors may be enhanced by their derivatization with peptide targeting ligands.
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Hammamy, M. Zouhir [Verfasser], and Torsten [Akademischer Betreuer] Steinmetzer. "Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3 protease / M. Zouhir Hammamy. Betreuer: Torsten Steinmetzer." Marburg : Philipps-Universität Marburg, 2014. http://d-nb.info/1064097413/34.
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Åberg, Veronica. "Peptidomimetics based on ring-fused 2-pyridones : probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-909.
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This thesis describes the synthesis and biological evaluation of highly substituted, ring-fused 2-pyridones. The utility of the bicyclic 2-pyridones to gain fundamental insights into the disease processes of bacterial infections and Alzheimer’s disease has been investigated. The 2-pyridones have mainly been studied as a new class of anti-infective agents termed pilicides. The function of the pilicides has been explored using uropathogenic E. coli (UPEC) as a prototype pathogen and urinary tract infection as a model disease. The pilicides target the infectious ability of UPEC by inhibiting key proteins (chaperones) in the so-called chaperone-usher pathway, thus preventing the assembly of bacterial surface organelles (pili/fimbriae). Synthetic pathways to aminomethylate the 2-pyridones have been developed in order to increase their aqueous solubility while retaining biological activity. Also, the importance of a carboxylic acid has been demonstrated in studies with various carboxylate derivatives and by bioisosteric replacement. Moreover, synthetic procedures to extend the backbone of the rigid, dipeptide-mimicking 2-pyridones have been established. This rendered peptidomimetic building blocks and structures that alongside their potential use as pilicides are of more general interest in peptidomimetic-related research. The potential pilicides have been screened for chaperone affinity using relaxation-edited 1H-NMR spectroscopy. In addition, their ability to inhibit pilus biogenesis in E. coli has been demonstrated by assays of hemagglutination, biofilm formation and attachment to bladder cells, as well as with electron and atomic force microscopy. Moreover, it has been confirmed that pilicides regulate the expression of pili without affecting the biofunctional properties of the pilus rod. This was verified by measurements of individual P pili, on living bacteria, using force measuring optical tweezers. The pilicide binding site was investigated using NMR spectroscopy and X-ray crystallography of a pilicide-chaperone complex. Based on the results obtained, a mechanism whereby the pilicides may inhibit pilus assembly was proposed, which was subsequently experimentally supported by surface plasmon resonance assays and genetic analysis. Finally, based on the generic 2-pyridone scaffold, a new collection of substituted compounds has been synthesized and validated as inhibitors of Amyloid β (Aβ)-peptide aggregation, which has been suggested to be involved in Alzheimer’s disease.
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Alfaro-Lopez, Lorenzo Josue. "Development of new conformationally and topographically constrained p60(c-src) PTK inhibitors. Solution and solid-phase approaches for the synthesis of delta-opioid receptor peptidomimetic ligands." Diss., The University of Arizona, 1999. http://hdl.handle.net/10150/288981.
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Based on the efficient substrate for p60ᶜ⁻ˢʳᶜ protein tyrosine kinase (PTK) YIYGSFK (1) (K(m) = 55 μM) obtained by combinatorial methods, we have designed and synthesized a series of conformationally and topographically constrained substrate-based peptide inhibitors for this enzyme. The inhibitors showed IC₅₀ values in low micromolar range (0.1-3 μM). A "rotamer scan" was performed by introducing four stereoisomers of β-Me(2')Nal in the postulated interaction site of peptide inhibitor (23) Y-c[D-Pen-(2')Nal-GSFC]KR-NH₂ (IC₅₀ = 1.6 μM). We found that the χ¹ space constraints imposed by the specialized amino acids, introduced at position 3 of peptide 23, were not as important as the configuration of the Cᵅ of that residue to recognize the active site of Src and Lck PTK, as reflected on the observed selectivity ratios. Cocrystallization studies between Lck and two of our inhibitors are in progress, in a collaboration with Dr. X. Zhu (Kinetix, Pharmaceuticals, Inc.). The results obtained may serve as the basis for the design of Lck and/or Src inhibitors, either peptide or nonpeptide. SL-3111 is a high affinity (IC₅₀ = 8.4 nM) and selective (μ/δ = 2020) δ-opioid receptor peptidomimetic ligand developed in Dr. Hruby's laboratory, as the result of extensive structure-activity relationship (SAR) studies based on peptide leads. However, bioassays (GPI and MVD) and in-vivo antinociception studies on the racemic mixture and both enantiomers of this compound, have shown particular problems such as low potency and toxicity. We have shown the importance of the piperazine ring in this molecule for binding toward the δ-opioid receptor. Thus, maintaining such scaffold we have studied a series of solution and solid-phase approaches toward the synthesis of SL-3111 analogues, which explore wider functional diversity at this heterocyclic ring. Compounds 64-67 were synthesized by solution methods. Analysis of the biological data and molecular modeling studies of these compounds, revealed an interesting trend in terms of the effects of the substituent at position two of the piperazine scaffold. Three different solid-phase protocols were explored toward the development of a combinatorial library of this type of compounds, which may facilitate future SAR studies.
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Mamone, Marius. "N-fluoroalkyles et CF3-cyclopropanes; vers de nouvelles unités peptidomimétiques." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS276.
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Grâce à des propriétés physico-chimiques particulières, le fluor prend de plus en plus d’importance dans la chimie médicinale et plus particulièrement dans les peptidomimétiques. Dans ce mémoire, deux classes de peptidomimétiques fluorées ont été étudiées.Dans la première partie, de nouveaux groupements N-Rf ; les hydrazines difluoro ou trifluorométhylées et les 1,2,3 triazoles N-difluorométhylés ont été préparés et des études de leurs propriétés structurales ont montré l’intérêt de l’incorporation du fluor sur la conformation des pseudopeptides via des interactions NH-F.Dans la seconde partie, de nouveaux peptidomimétiques comportant des groupements cyclopropanes trifluorométhylés ont été conçus et synthétisés en tant qu’inhibiteurs potentiels du protéasome 26S (un macro-complexe protéique impliqué dans la dégradation de nombreuses protéines intracellulaires et qui a fait ses preuves en tant que cible pour le traitement de cancers)Through special physico-chemical properties, fluorine is becoming increasingly important in medicinal chemistry and particularly in peptidomimetics. In this paper, two classes of fluorinated peptidomimetics were studied.In the first part, new N-Rf moieties; difluoro or trifluoromethylated hydrazines and N-difluoromethyl 1,2,3 triazoles were prepared and the study of their structural properties have shown the benefit of the incorporation of fluorine on the conformation of the peptidomimetics via NH-F interactions.In the second part, new trifluoromethylated cyclopropanes containing peptidomimetics were designed and synthesized as potential inhibitors of the 26S proteasome, a macro-complex protein involved in the degradation of many intracellular proteins and which has been recognized as a target for cancer treatment
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DaSilva, Thiago Gaspar. "CHARACTERIZATION OF PROTEIN PRENYLTRANSFERASES AND PROTEIN PRENYLATION IN PLASMODIUM FALCIPARUM." Master's thesis, University of Central Florida, 2004. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/4401.
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Malaria kills at least one million people each year, mostly children - a death every 30 seconds. Almost one half of the world population is at risk from malaria. Antimalarial drugs are the only means for the treatment of about 500 million annual global malaria cases. Because of prevalent drug-resistance it is extremely urgent to identify new drug targets. Many proteins involved in eukaryotic signal transduction and cell cycle progression undergo post-translational lipid modification by a prenyl group. Protein prenyltransferases, which catalyze the post-translational prenyl modification, have been established as a target for anticancer therapy. Research done in our laboratory has demonstrated recently that prenyl modification of proteins could be a novel target for the development of antimalarial drugs.The goal of this study is to understand the molecular mechanism of protein prenylation in Plasmodium. The key to use of prenyltransferase inhibitors for the pharmacological intervention is a thorough understanding of the in vivo prenylation pathways in the malaria parasite. Knowledge of the physiological functions of the cellular protein substrates of malarial prenyltransferases is an important first step in the elucidation of the mechanism of antimalarial action of inhibitors of protein prenylation. The research described in this thesis revealed the evidence for the existence of farnesylated and geranylgeranylated malaria parasite proteins. The study shows that the dynamics of protein prenylation changes with the intraerythrocytic development cycle of the parasite. We detected that prenylated proteins in the 50 kDa range were mostly farnesylated and that the proteins in the 22-25 kDa range were mostly geranylgeranylated. The prenylation of P. falciparum proteins is inhibited by prenyltransferase inhibitors. We have also demonstrated unique features of protein prenylation in P. falciparum compared to the human host such as farnesylation of proteins are sensitive to inhibition by geranylgeranyltransferase inhibitors.. In-silico search of the malarial genome sequence identified potential protein prenyltransferase substrates. One of these substrates is a SNARE protein Ykt6 homologue. The malarial Ykt6 was recombinantly expressed and subjected to an in-vitro prenylation assay. We showed that the recombinant Ykt6 was indeed a substrate for the malarial prenyltransferase.M.S.
Department of Molecular Biology and Microbiology
Health and Public Affairs
Molecular Biology and Microbiology
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Levesque, Christine. "Développement d’inhibiteurs pharmacologiques de PACE4 pour le traitement du cancer de la prostate." Thèse, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/6013.
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Résumé : La protéolyse par les proprotéines convertases (PC) représente une étape cruciale de maturation pour de nombreux peptides et protéines destinés aux voies de sécrétions cellulaires. Parmi ces substrats des PC, de nombreuses molécules participent aux étapes clés de progression tumorale. L’enzyme PACE4, une des PC, est d’ailleurs surexprimée dans le cancer de la prostate et des études antérieures réalisées dans notre laboratoire démontrent que cette protéase occupe un rôle essentiel et non redondant dans la progression du cancer de la prostate. Puisque PACE4 représente une cible thérapeutique potentielle pour le traitement du cancer de la prostate, l’objectif principal des travaux présentés dans cette thèse vise à développer un inhibiteur pharmacologique de PACE4 et d’évaluer son potentiel thérapeutique. Le développement d’inhibiteur spécifique à la PACE4 représente un défi de taille, puisque le site actif des PC démontre un fort niveau d’homologie. Bien que les sous-sites S1 à S4 des PC soient hautement conservés, la littérature suggère qu’il existe des déterminants moléculaires exploitables au sein des sous-sites S5 à S8. Ainsi, ces observations suggèrent qu’une sélectivité d’inhibition pourrait provenir de courts peptides. En analysant les profils d’inhibition obtenus pour divers peptides inhibiteurs des PC, la séquence Ac-LLLLRVKR-NH[indice inférieur 2], nommée Multi-Leu, a été identifiée comme inhibiteur permettant d’obtenir une préférence d’inhibition 20 fois plus importante pour PACE4 que pour Furine. Dans le but d’améliorer les propriétés pharmacocinétiques du composé et permettre son utilisation comme inhibiteur pharmacologique, des études de relation structure-activité ont été conduites. Ces études ont permis de déterminer que le peptide Multi-Leu est sujet à une dégradation par des exopeptidases, et par conséquent l’addition d’acides aminés non naturels aux extrémités N et C-terminales permet d’augmenter la stabilité du composé. Suivant cette étude, la modification amidinobenzylamide (Amba) a été introduite en position P1, permettant d’augmenter la puissance d’inhibition du composé, ainsi qu’un stéréoisomère D-Leucine en position P8. La caractérisation du potentiel inhibiteur du peptide Ac-[DLeu]LLLRVK-Amba démontre l’efficacité du peptide in vivo alors qu’une administration par voie intra veineuse du composé parvient à freiner la progression tumorale dans un modèle de xénogreffes de cancer de la prostate. Dans ce modèle, l’analogue du peptide Multi-Leu parvient à bloquer la néovascularisation tumorale en plus d’induire la quiescence et l’apoptose dans les tumeurs traitées. // Abstract : Numerous secreted peptides or proteins require a proteolytic activation by the proprotein convertases (PC) to fully gain their biologic activities. Among substrates of the PC family, there exist various cancer-related molecules. The enzyme PACE4, one of the seven kexinlike PC has been demonstrated to be overexpressed in prostate cancer and to have a nonredundant role in prostate cancer progression. Since PACE4 is a validated therapeutic target for prostate cancer, the main aim of this thesis was to develop a pharmacologic PACE4 inhibitor and to evaluate its therapeutic potential. The development of PACE4 specific inhibitors represents a challenge since PC share an important homology level within their active site. Whereas S1 to S4 subsites appear to be highly homologous within the PC family, litterature suggests that significant differences exist in subsites S5 and beyond, suggesting that peptide compound could result in specific inhibitors. In this thesis, the Multi-Leu peptide (Ac-LLLLRVKR-NH[subscript 2]) was identified as a selective PACE4 inhibitor, which displays a 20-fold inhibitory preference toward PACE4 over furin. In order to improve Multi-Leu peptide pharmacokinetic profile, structureactivities relationship studies were performed and allowed for the identification of two modifications that increase both inhibitory properties and stability of this molecule. Peptide resulting from introduction of an arginine mimetic residue amidinobenzylamide (Amba) in P1 and a stereoisomer D-Leucine in position P8 displayed an improved pharmacokinetic profile. Futhermore, intravenous administration of the compound Ac-[DLeu]LLLRVKAmba significantly inhibited prostate cancer progression in a LNCaP xenograft model of prostate cancer. This Multi-Leu peptide analog also inhibited tumor neovascularisation along with inducing cell quiescence and apoptosis in tumors of treated animals.
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Bunga, Flora. "Synthesis of cyclic peptide natural products and peptidomimetics." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675730.
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Chitin, a linear polymer of N-acetylglucosamine, is an essential structural component of fungal, nematode and insect pathogens but is not found in human physiology. Chitinases, which hydrolyze this polymer, play a key role in life cycle of these pathogens and associated pathogenesis. Consequently chitinase inhibitors have generated a lot of interest given their potential as insectides, fungicides and antimalarials. Herein, approaches are reported to the synthesis of some non-sugar based chitinase inhibitors: the cyclic pentapeptide natural products argifin, banyasin A and diketopiperazines related to the natural product CI-4. In order to improve the efficiency of production of argifin and facilitate SAR on analogues of the natural product, a revised synthesis of argifin has been developed. The synthesis of argifin was carried out by a combination of solid-phase and solution chemistry. The assembly of the linear peptide was carried out by SPPS and the cyclisation was performed in solution. The protecting groups chosen for the Asp and Arg residues were removable by hydrogenolysis, as this allowed aspartimide formation under acidic conditions to be avoided. Only one HPLC purification was required at the final step; argifin was isolated in 19% yield, compared to 18% yield for the first synthesis by Dixon et al. Banyasin A contains the same essential Arg(MC)-MePhe dipeptide motif as argifin and so it is of considerable interest as a potential Family 18 chitinase inhibitor. The synthesis of Amoa (3-amino-2-methyl-5E-octenoic acid) a rare amino-acid present in banyasin A was investigated. An advanced intermediate for the synthesis of Amoa was successfully obtained via chiral pool chemistry in an 8 step sequence from L-Asp. This involved preparation of a selectively protected β-methyl-substituted Asp derivative, which was then homologated to the β-amino-acid via Arndt-Eistert chemistry to give (3R,4R)-3-(((benzyloxy)carbonyl)amino)-4-methyl-5-oxo-5-allyloxypentanoic acid in 27% yield for the final step. The cyclic dipeptide CI-4, cyclo (L-Arg-D-Pro) is a weak inhibitor (IC50 = 1.2 mM) of Family 18 chitinases, however its binding efficiency index (BEI) is comparable to more potent inhibitors such as argifin. Some analogues of CI-4 show promising activity against a typical bacterial type Family 18 chitinase, SmChiB1 from Serratia marcescens. The cyclic dipeptide should therefore be a useful starting point for the development of more effective and selective inhibitors of this enzyme class. A series of cyclo (Xaa-Pro)-based dipeptides were synthesized, with different Xaa such as L/D-Pro, Gly, L-Ser, L/D-Arg, D-His, D-Phe, with yields ranging from 12 to 84%. Preliminary biological data confirm that cyclo(D-Xaa-D-Pro) may be a novel template for the development of new drug-like inhibitors of Family 18 chitinases.
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Hu, Yaogang. "Design and Synthesis of Bioactive Peptidomimetics." Scholar Commons, 2015. https://scholarcommons.usf.edu/etd/5504.
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Protein-Protein Interactions (PPIs) play a very important role in biological functions and therefore the inhibition of specific Protein-Protein Interactions has a huge therapeutic value. The most successful small molecular PPIs inhibitors do not fit with the prevalent `Rule of Five' drug profile. To overcome the disadvantages of small molecular PPIs inhibitors, peptide based PPIs inhibitors were developed. Herein we describe the development of a new class of peptidomimetics AA-peptides. The AApeptides were designed based on chiral PNA backbone. Substitution of nucleobases yields AApeptides that are resistant to proteolysis and capable of mimicking peptides. Two types of AApeptides were discussed in this dissertation "α-AApeptides" and "γ-AApeptides". The AApeptides were shown to disrupt p53/MDM2 protein-protein interaction and tomimic fMLF tripeptide to target G protein-coupled formyl peptide receptors (FPRs). Moreover, the lipidated α-AApeptides can mimic the structure and function of natural antimicrobial lipopeptides and show broad-spectrum activity against both Gram-positive and Gram-negative bacteria. Lastly I have designed and synthesized a serials of phosphopeptides to disrupt cancer related STAT3-STAT3 dimerization.
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Formicola, Lucia. "Design of peptidomimetics towards new foldamers and 26S proteasome inhibitors." kostenfrei, 2008. http://epub.uni-regensburg.de/13410/.
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Fanelli, Roberto. "Design and synthesis of new peptidomimetics as potential inhibitors of HIV-1 protease." Paris 11, 2010. http://www.theses.fr/2010PA114855.
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La protéase du VIH est responsable de la transformation post-traductionnelle des polyprotéines virales et, par conséquence, de la production de protéines structurales et fonctionnelles. Pour cette raison elle représente une cible importante pour le traitement du SIDA. La protéase du VIH-1 est une aspartyl-protéase qui n’est active que sous sa forme homodimérique. Chaque chaîne est constituée de 99 acides aminés et le site actif se situe à l’interface entre les deux unités monomériques. Les inhibiteurs de la protéase actuellement disponibles dans le commerce ont comme cible ce site actif, mais les mutations qui peuvent être présentes, soit à l’intérieur qu’à l’extérieur de celui-ci, peuvent entraîner l’apparition de phénomènes de résistance vis-à-vis de ces composés. L’objectif de ce travail de thèse a été le développement et la synthèse de peptides et de peptidomimétiques comme potentiels inhibiteurs de la protéase, capables de contourner la résistance et de constituer ainsi une alternative aux inhibiteurs du site actif. Deux approches différentes ont été suivies. La première approche, décrite au chapitre 2, s’intéresse au repliement du monomère de la protéase. Ce mécanisme suit une succession hiérarchique d’événements à partir de la formation de structures nommées LES (Local Elementary Structure) qui contiennent une séquence d’acides aminés hautement conservée. L’interaction entre deux LES complémentaires représente la première étape du mécanisme. Puisque ces LES ont un rôle si important pour la protéine, le virus ne peut pas se permettre leur mutation. Nous avons décrit la synthèse de peptides ayant la même séquence que ces régions critiques (p-LES), ainsi que la synthèse de peptidomimétiques analogues au p-LES qui pourraient se lier à la région complémentaire en empêchant un repliement correct de la protéine. La seconde approche, décrite au chapitre 3, consiste dans le développement et la synthèse de composés mimétiques du feuillet b antiparallèle terminal de la protéase du VIH-1. La forme dimérique de la protéase du VIH-1 est stabilisée par le feuillet b antiparallèle, formé par les brins N- et C- terminaux de la protéine. Des molécules rigides, appelées pinces moléculaires et basées sur une structure naphtalénique à laquelle sont liées via un espaceur propylcarboxyilique deux chaines peptidomimétiques, sont capables d’empêcher la dimerisation de la protéine avec, comme conséquence, une perte de l’activité. Dans ce travail de thèse, nous nous sommes intéressés à la réduction du caractère peptidique de ces pinces moléculaires et à l’augmentation de leur hydrosolubilité. Dans ce but, nous avons conçu deux stratégies différentes : 1) la synthèse de nouveaux bras peptidomimétiques à hydrophilie augmentée et 2) l’introduction de groupements hydrophiles sur l’espaceur naphtalène, principalement grâce à des réactions catalysées par des métaux de transition. Nous décrivons ici, la synthèse et l’activité inhibitrices de ces nouvelles pinces moléculaires sur les protéases du VIH-1 sauvage et mutéeBeing HIV-1 protease responsible for the post-translational processing of the viral polyproteins and the subsequent generation of the structural and functional proteins, it is an important target for the treatment of AIDS. HIV-1 protease is an aspartyl protease active as an homodimer. Every single chain is built of 99 amino acids and the active site is at the interface between the two monomeric units. The commercially available protease inhibitors target the active site but several mutations within or outside the active site led to the emergence of resistance to these compounds. This thesis deals with the design and synthesis of peptides and peptidomimetics as potential inhibitors of HIV-1 protease that can circumvent drug resistance and that can be alternatives to active site PR inhibitors. Two different approaches were applied to reach our target. The first one, described in chapter 2, deals with the folding of the protease monomer that proceeds following a hierarchical succession of events starting from the formation of local elementary structures (LES), which contain highly conserved amino acids. The interaction between two complementary LES represents the first step of the folding process. Since these LES are so important for the protein, the virus can not afford their mutation. We describe here the synthesis of small peptides with the same sequence as one of these critical regions (p-LES) and of peptidomimetics analogues to the p-LES that could bind to the complementary region preventing the correct folding. CD studies of interaction between synthesized peptides and native sequence of the protease are presented. The second approach, described in chapter 3, consists in the design and synthesis of compounds mimetics of the terminal -sheet of the HIV-1 protease. The dimeric form of HIV-1 protease is stabilized by the antiparallel -sheet formed between the C- and N-terminal regions of the protein. Constrained molecular tongs based on a naphtalene scaffold in which peptidomimetic strands are attached through a carboxylpropyl link disrupt the dimeric enzyme with loss of activity. We are now concerned in decreasing the peptidic character and increasing the hydrosolubility of the molecular tongs. For that purpose, we have conceived two different strategies: 1) the synthesis of new peptidomimetic strands with increased hydrophilicity and 2) the introduction of hydrophilic groups on the scaffold mainly via metal-catalyzed cross coupling reactions. We describe here the synthesis and the biological activity against wild-type and mutated HIV-1 protease of these new molecular tongs
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Bordessa, Andrea. "Design, synthesis and structural evaluation of peptidomimetics towards foldamers, PNAs and non covalent inhibitors of the 20S proteasome." kostenfrei, 2008. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1112/.
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Blomberg, David. "Synthesis of β-turn and pyridine based peptidomimetics." Doctoral thesis, Umeå universitet, Kemi, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1104.
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Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.
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Ella-Menye, Jean-Rene. "Synthesis of Novel Chiral Heterocyclic Compounds for Antibacterial Agents and Peptidomimetics." ScholarWorks@UNO, 2007. http://scholarworks.uno.edu/td/611.
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Small chiral molecules are very important building blocks in the synthesis of biologically active compounds. These building blocks include nitrogen and oxygen-containing heterocycles such as 2-oxazolidinones, 1,3-oxazinan-2-ones, 2-oxazolines, oxazines, morpholine and morpholinones. Because of their interesting properties, chiral heterocycles have stirred great interest in the synthetic chemist community to develop useful and efficient strategies to these molecules. In this dissertation, the design and syntheses of various heterocyclic building blocks are presented, as well as the testing of their biological activities as antibacterial. Another very interesting family of heterocycle-containing molecules are the Aeruginosins. They are a family of marine natural products isolated from a blue-green algae, which display inhibitory activity against serine proteases such as thrombin, trypsin, and factor VIIa. Most aeruginosins contain an heterocyclic moiety called the 2-carboxy-6-hydroxyoctahydroindole (Choi) ring; this Choi moiety is a rigid bicyclic unnatural amino acid and is the core structure in the aeruginosins, indispensable to their biological activity. A synthesis of a ring-oxygenated variant of the Choi from D-mannose is reported in this dissertation. The ring-oxygenated variant of 2-carboxy-6-hydroxyoctahydroindole can potentially be used as a surrogate of Choi in the design and synthesis of aeruginosin-based thrombin inhibitors.
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Lecointre, Bertrand. "Functionalization of pyridine N-oxide - Peptidomimetics based on the imidazole motif used as Histone Deacetylase inhibitors." Rouen, 2014. http://www.theses.fr/2014ROUES012.
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L'objectif principal de ce document sera de détailler la substitution de pyridine N-oxyde dans un premier temps puis la synthèse d'inhibiteurs d'Hisotone Déacétyléase. Nous allons successivement présenter une partie introductive dans laquelle nous nous attarderons sur la synthèse de dérivés pyridiniques et quinoléiniques en vue de l'accès à des composés de type 5, 6, 7, 8-tetrahydroquinoline et d'une étude d'ortholithiation. Dans une seconde partie, nous nous attarderons sur l'intérêt des peptidomimétiques et leurs utilisations en chimie pharmaceutique en citant quelques exemples de molécules bioactives. Dans cette même partie, nous traiterons ensuite l'enzyme HDAC et développerons deux points principaux que sont à la fois le rôle qu'elle joue dans notre organisme ainsi que la structure et le mode d'action de ses inhibiteurs. Puis nous exposerons la synthèse de nos peptidomimétiques ainsi que leur activité biologiqueThe main objective of this manuscript will be to detail the functionalization of pyridine N-oxide. After a bibliographic introduction we will study the functionalization of pyridine and quinoline N-oxide by carbon nucleophile, in order to synthetize 5,6,7,8-tetrahydroquinoline and make an ortho-lithiation study. In a second part we will detail the synthesis of peptidomimetics based on the imidazole motif used as histone deacetylase inhibitors. First we will expose the interest of the peptidomimetics. Afterwards we will explain the role of the histone deacetylase enzyme and its main inhibitors. Finally we will expose the synthesis of our peptidomimetics and their biological activity
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Akula, Kavitha. "Expanding the Spiroligomers Toolbox as Protein-Protein Interaction Inhibitors." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/422281.
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ChemistryPh.D.
This work presents the application of spiroligomers as inhibitors of protein-protein interactions. After the discovery of an acyl-transfer coupling reaction by Dr. Zachary Brown, a previous graduate student of Schafmeister group, the synthesis of highly functionalized spiroligomers that mimic the helical domain of p53 was undertaken before each molecule was tested for binding to HDM2, a natural binding partner of p53. A library of molecules was synthesized on solid support that altered the stereochemistry along the spiroligomer as well as the presented functional groups. It was determined that spiroligomers enter human liver cancer cells through passive diffusion and induces a biological response in both a dose- and time-dependent manner. The synthesis of additional spiroligomer analogues achieved low micromolar to high nanomolar range activity during screening in direct and competitive binding assays. In parallel to the project above, a series of spiroligomers that mimic the side chains of the leucine zipper region of Max were synthesized in an effort to disrupt the interaction of the protein with c-Myc. The series of compounds contained various stereocenter combinations and different functional groups as before but were made in solution before testing for inhibition. Initial binding assays resulted in low micromolar activity, however, secondary assays (ELISA and cellular assays) did not confirm the inhibitory effect of spiroligomers on the c-Myc/Max heterodimer. In summary, this work illustrates that spiroligomers are capable mimics of helical peptides and can induce a biological response.
Temple University--Theses
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Neffe, Axel T. "Design, Synthese und Analyse CD4-bindender Peptidomimetika Entwicklung von HIV-Entry-Inhibitoren /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=970660677.
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Lampa, Anna. "Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease." Doctoral thesis, Uppsala universitet, Avdelningen för organisk farmaceutisk kemi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-163361.
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Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease. The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.
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Al-Horani, Rami. "Designing Direct and Indirect Factor Xa Inhibitors." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/329.
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Anticoagulants are the basis for treatment and prevention of thrombotic diseases. The currently available medicines are associated with a wide range of adverse reactions that mandates developing new anticoagulants. Several lines of evidence support the superiority of factor Xa (FXa) as a promising target to develop novel anticoagulants. This work focuses on the design of direct and indirect FXa inhibitors using an interdisciplinary approach. As indirect FXa inhibitors, a focused library of tetrasulfated N–arylacyl tetrahydroisoquinoline (THIQ) nonsaccharide allosteric antithrombin activators was designed, synthesized, and biochemically evaluated to establish their structure–activity relationship (SAR). An N–arylacyl THIQ analog having carboxylate at position–3, two sulfate groups at positions–5 and –8 of THIQ moiety, butanoyl linker, and two sulfate groups at positions–2 and –5 of the phenolic monocyclic moiety was identified as the most promising nonsaccharide antithrombin activator with KD of 1322 ± 237 μM and acceleration potential of 80–fold. Its biochemical profile indicates a strong possibility that it activates antithrombin by the pre–equilibrium pathway rather than the induced–fit mechanism utilized by heparin analogs. A similar interdisciplinary approach was exploited to design direct FXa inhibitors that possess high selectivity and are potentially orally bioavailable. Structurally, the designed direct FXa inhibitors are neutral THIQ dicarboxamides. THIQ dicarboxamide is a privileged structure with a semi–rigid character, a structural feature that potentially offers high selectivity for targeting FXa over other coagulation and digestive proteases. It can also be thought of as an amino acid–like structure, which affords accessibility to a large number of compounds using well established peptide chemistry. Mechanistically, the designed inhibitors were expected to bind to FXa in the active site and function as orthosteric inhibitors. These direct FXa active site inhibitors are also likely to inhibit clot–bound enzyme. Nearly 60 THIQ dicarboxamides were synthesized and biochemically evaluated. Through detailed SAR analysis, the most potent analog was designed and found to exhibit an IC50 of 270 nM (Ki = 135 nM), an improvement of more than 207–fold over the first inhibitor synthesized in the study. The most potent inhibitor displayed at least 1887–fold selectivity for FXa over other coagulation enzymes and a selectivity index of at least 279–fold over the digestive serine proteases. This analog doubled plasma clotting times at 17–20 μM, which are comparable to those of agents being currently studied in clinical trials. Overall, allosteric and orthosteric approaches led to the design of indirect and direct small molecule inhibitors of FXa based on the THIQ scaffold. This work introduces two promising molecules, a tetrasulfated N–arylacyl THIQ analog as a heparin mimetic and a neutral THIQ dicarboxamide as a potent, selective, and potentially bioavailable peptidomimetic, for further advanced medicinal chemistry studies.
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Andersson, Hanna. "Design and Synthesis of Angiotensin IV Peptidomimetics Targeting the Insulin-Regulated Aminopeptidase (IRAP)." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-122218.
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Brahm, Kevin [Verfasser], Katja [Akademischer Betreuer] Schmitz, and Harald [Akademischer Betreuer] Kolmar. "Untersuchung von Peptidomimetika als Inhibitoren für das Chemokin CXCL8 / Kevin Brahm ; Katja Schmitz, Harald Kolmar." Darmstadt : Universitäts- und Landesbibliothek Darmstadt, 2020. http://d-nb.info/1211726185/34.
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Wang, Xiaodong. "Design, Syntheses, and Bioactivities of Conformationally Locked Pin1 Ground State Inhibitors." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/26625.
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Pin1 (protein interacting with NIMA 1) is a peptidyl-prolyl isomerase involved in mitosis. As a potential anti-cancer drug target, Pin1 interacts and regulates the activity of an increasing number of cell cycle enzymes by an unknown mechanism. These cell cycle enzymes include Cdc25, Cdc27, Cyclin D1, Myt1, Wee1, NIMA, Cdc2, Plk1 and c-Myc. Recent research has revealed that Pin1 is overexpressed in a variety of cancer cell lines and Pin1 inhibitors inhibit proliferation activity of several cancer cells overexpressing Pin1. The most potent Pin1 inhibitors identified so far are in the micromolar range and no pharmacophore has been identified.
In order to assist the understanding of the biological function of Pin1 using molecular probes, two amide isosteres of Ser-trans-Pro and Ser-cis-Pro dipeptides were designed and stereoselectively synthesized. The conformationally locked Ser–trans–Pro mimic, Boc-SerΨ[(E)CH=C]Pro–OH, was synthesized through the use of an Ireland-Claisen [3,3]-sigmatropic rearrangement in nine steps with 13% overall yield from a serine derivative. The Ser-cis-Pro mimic, Boc-SerΨ[(Z)CH=C]Pro–OH, was synthesized through the use of a Still-Wittig [2,3]-sigmatropic rearrangement in 11 steps with an overall yield of 20% from the same starting material.
Conformationally locked peptidomimetics, including two exactly matched peptidomimetics, Ac–Phe–Phe–pSer–Ψ(E)CH=C]Pro–Arg–NH2 and Ac–Phe–Phe–pSer–Ψ[(Z)CH=C]Pro–Arg–NH2, were synthesized from these Ser-Pro isosteres using Fmoc SPPS. A protocol for in vitro Pin1 inhibition assay was established for measuring the inhibition constant for these peptidomimetics. A conformationally locked cis peptidomimetic inhibits Pin1 with a Ki of 1.7 μM, 23-fold more potent than its trans counterpart, illustrating the preference of Pin1 for a cis amide bond in its PPIase domain. The A2780 ovarian cancer cell antiproliferation activity of these peptidomimetics parallels their respective Pin1 inhibition data. This research provides a start toward more drug-like Pin1 inhibitor design. Gly–trans–Pro isosteres were synthesized using the Ireland-Claisen route. The construction of a non-peptidic (Z)-alkene library for Pin1 inhibition was attempted using the Ser-cis-Pro mimic, Boc—SerΨ[(Z)CH=C]Pro–OH as the core.Ph. D.
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Weiss, Stephanie Tara. "The theoretical modeling, design, and synthesis of key structural units for novel molecular clamps and pro-apoptotic alpha helix peptidomimetics." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001475.
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Aitken, Steven Geoffrey. "Design, synthesis and testing of β-strand mimics as protease inhibitors." Thesis, University of Canterbury. Chemistry, 2006. http://hdl.handle.net/10092/1984.
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Chapter 1 gives background information on proteases and discusses the concept of protease inhibition as a therapeutic strategy for humans. It introduces the key concept that conformation defines biological activity. It also outlines how proteases almost universally bind their substrate/inhibitors in an extended β-strand conformation. The use of calpain as a prototype protease for the testing of β-strand mimics synthesised later in the thesis is also discussed. Chapter 2 describes how molecular modeling was used to rationalise the structure based activity relationships (SAR) of known calpain inhibitors. Molecular modeling was then used to successfully design a number of acyclic β-strand mimics. The synthesis and testing of eight such inhibitors is described. The most potent β-strand mimic prepared was 2.13. This was determined to have an IC₅₀ of 30 nM against calpain II. Chapter 3 outlines the history and application of ring closing metathesis (RCM) to the synthesis of cyclic compounds. The attempted synthesis of an eight membered cyclic nitrogen to nitrogen conformationally constrained dipeptide is described. The synthesis of a conformationally constrained β-amino acid calpain inhibitor (3.73) is also described. A novel calpain inhibitor motif was designed in Chapter 4. On the basis of this an in-silico combinatorial library of two hundred and eighty eight possible β-strand templates was prepared. Conformational analysis of this library was performed and from this a number of excellent β-strand templates were identified and selected for synthesis. The preparation of ten β-strand templates is described. New microwave irradiation methodology was developed to achieve this. vii The formation of a six-membered catalyst deactivating chelate is also proposed to explain why some dienes fail to undergo RCM. Two methods to circumvent the formation of such a chelate are outlined. The addition of Lewis acid chloro-dicyclohexyl borane to the RCM reaction mixture and chain length alteration are investigated. Chapter 5 describes the design of macrocyclic β-strand mimics using induced fit molecular modelling. The physicochemical properties of these were calculated in-silico. From this analysis a number of Tyr-XX-Gly based and Tyr-XX-Cys based macrocyclic calpain inhibitors were selected for synthesis. The preparation and testing of these are described. In the Tyr-XX-Gly macrocyclic system a number of variables were investigated and numerous SAR implications concluded. Aldehyde 5.14 was identified as the best electrophilic warhead macrocyclic calpain inhibitor with an IC₅₀ against calpain II of 27 nM. The best non-electrophilic warhead macrocycle (5.13) had an IC₅₀ against calpain II of 704 nM. Chapter 6 describes synthetic optimisation for the preparation of calpain inhibitors 2.13, 5.14 and 5.17. Multi-gram quantities of each were prepared. Aldehydes 2.13 and 5.14 were evaluated as anti-cataract agents using in-vivo cataract sheep model. Both of these β-strand mimics were demonstrated to retard cataract development. Macrocycle 5.14 was found to be the most effective, decreasing the rate of cataract development between forty four and forty nine per cent relative to control. Chapter 7 outlines the attempted development of RCM methodology for the chiral synthesis of α-α disubstituted amino acid lactams. In addition, methodology for the stereoselective incorporation of a C-N constrained β-amino acid carbocycle into a peptide or peptidomimetic is described.
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Lu, Yinghui [Verfasser], and Wolfgang [Akademischer Betreuer] Garten. "Potent inhibition of highly pathogenic influenza virus infection using a peptidomimetic furin inhibitor alone or in combination with conventional antiviral agents / Yinghui Lu. Betreuer: Wolfgang Garten." Marburg : Philipps-Universität Marburg, 2014. http://d-nb.info/1059856115/34.
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Pemberton, Nils. "Synthesis and functionalization of ring-fused 2-pyridones : Targeting pili formation in E. coli." Doctoral thesis, Umeå : Department of Chemistry, Umeå Universitet, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1416.
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Keita, Massaba. "Conception, synthèse et évaluation biologique d'inhibiteurs fluorés non covalents du protéasome." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-01059792.
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Le protéasome 26S est une macromolécule impliquée dans la dégradation de la majorité des protéines cellulaires. Parmi ces protéines, il y a les différents régulateurs de processus cruciaux tels que les protéines responsables de la progression du cycle cellulaire, de l'apoptose, des réponses inflammatoires, de l'activation de NF-B, de la présentation antigénique et de la différenciation cellulaire. Par conséquent, les inhibiteurs du protéasome sont des agents thérapeutiques dans des pathologies tels que le cancer, l'inflammation et les maladies auto-immunes. En effet, les inhibiteurs du protéasome sont connus pour induire la mort sélective des cellules cancéreuses tout en les rendant plus sensibles aux autres traitements anticancéreux existants (chimiothérapie, radiothérapie...). L'objectif de notre laboratoire est de développer des inhibiteurs non covalents du protéasome de structures peptidomimétiques fluorés ou non fluorés, et de montrer l'intérêt du fluor en chimie médicinale. Mon projet de thèse s'inscrit dans ce cadre. Dans un premier temps nous avons mis en évidence la grande diversité et la quantité des inhibiteurs du protéasome montrant ainsi l'importance de cette macromolécule comme cible dans le traitement du cancer. D'ailleurs, deux de ces inhibiteurs sont utilisés dans le traitement du myélome multiple et du lymphome du manteau et, plusieurs composés sont en études cliniques pour différents cancers. Nous avons aussi mis en évidence le bénéfice apporté par l'incorporation de groupement fluoré sur une molécule bioactive en particulier dans les structures peptidomimétiques. En revanche, ce rappel bibliographique a aussi montré que les peptidomimétiques contraints et fluorés sont peu décrits dans la littérature et le seul exemple à notre connaissance est l'analogue contraint et fluoré de la substance P contenant le motif (Z)-fluoroalcène.La deuxième partie de ces travaux de thèse s'est focalisée sur la conception, la synthèse et l'évaluation biologique d'inhibiteurs originaux du protéasome. Nous avons mis au point une synthèse facile et efficace de pseudopeptides possédant les motifs α et β-hydrazino acides et le motif β-hydrazino acide trifluorométhyle (schéma 1). Ces molécules inhibent de manière efficace le site CT-L du protéasome du lapin avec une IC50 de l'ordre du submicromolaire. Nous avons ainsi démontré que l'activité biologique est maintenue en remplaçant un α-amino acide par un scaffold α ou β-hydrazino acide. La pharmacomodulation effectuée autour de ces motifs nous a permis d'établir des relations structure-activité. Nous avons aussi mis au point un modèle de docking assez fiable qui va nous permettre de prédire le potentiel inhibiteur de nos futures molécules.Enfin, nous avons déterminé l'IC50 de nos molécules en utilisant la technique du FABS en RMN du 19F. Schéma1: voies d'accès aux peptidomimétiques contenant les motifs α et β-hydrazino acide et le motif β-hydrazino acide trifluorométhyl.Ces travaux de thèses ont été complétés par une méthodologie de synthèse portant sur le développement de nouveaux synthons contraints fluorés dans le but de les incorporer dans nos inhibiteurs de protéasome. Les cyclopropanes trifluorométhyles ont été obtenus en utilisant la réaction tandem de Michael, addition nucléophile suivie de cyclisation avec une excellente diastéréosélectivité pour certaines réactions. Les cyclopropanes obtenus ont été fonctionnalisés en amino acides ce qui faciliterait leur incorporation dans nos pseudopeptides. Les N-aminoaziridines fluorés ont été synthétisés à partir d'oléfines fluorés et de précurseurs de nitrène en présence de diacétate d'iodobenzène (PhI(OAc)2. L'incorporation de ces nouveaux scaffolds dans la structure de nos inhibiteurs de protéasome est en cours de réalisation dans le laboratoire.
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Lesma, Jacopo. "β-Hairpin peptidomimetics as inhibitors of hIAPP amyloid protein aggregation : design, synthesis and evaluation Introducing sequential aza-amino acids units induces repeated ß-turns and helical conformations in peptides β-Hairpin peptide mimics decrease human Islet Amyloid Polypeptide (hIAPP) Aggregation." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ018.
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Le diabète de type 2 (DT2), qui compte plus de 400 millions de cas dans le monde, représente 90 % du nombre total de cas de diabète. T2D est une maladie dégénérative associée à la résistance à l’insuline et à la mort des β-cellules pancréatiques liées aux dépôts de la protéine amyloïde hIAPP (également appelée amyline), qui sont observés dans le pancréas de plus de 95 % des patients atteints de DT2. Les traitements actuellement disponibles sont symptomatiques et caractérisés soit par des effets secondaires significatifs, soit par un faible impact sur l’incidence des pathologies associées et la réduction de la mortalité. Ainsi, pour trouver un traitement étiologique contre DT2, le ciblage de hIAPP est devenu une stratégie prometteuse à explorer. À ce jour, peu de classes de composés ont été proposées pour inhiber le processus d’agrégation de hIAPP. Cependant, à notre connaissance, seuls de très rares exemples de β-hairpin acycliques ont été décrits. Puisque l’agrégation hIAPP est un processus très complexe et dynamique, nous avons émis l’hypothèse que desβ-hairpins flexibles pourraient mieux s’adapter aux différentes conformations de hIAPP formées au cours du processus d’agrégation. Notre conception a été basée sur différents β-turn flexibles constitué d’un motif pipéridino-pyrrolidine lié à deux bras différents inspirés de la séquence primaire du peptide hIAPP, avec un élément d’auto-reconnaissance peptidique (SRE) dérivé de la séquence amyloïdogène de hIAPP, et faisant face à une séquence de blocage peptidique ou peptidomimétique. Afin de confirmer la conformation en β-hairpin de nos inhibiteurs, la conformation de nos composés a été étudiée par RMN et dans quelques cas par une dynamique moléculaire. Ensuite, leur capacité à interférer avec le processus d’agrégation de hIAPP a été principalement évaluée par la spectroscopie de fluorescence à la thioflavine-T. Les composés les plus prometteurs de la série ont ensuite été étudiés par d’autres essais biophysiques comme la microscopie électronique à transmission (TEM), l’électrophorèse capillaire (CE) et l’IMS-MS. Les meilleurs composés de la série ont ensuite été étudiés pour déterminer leur capacité à réduire la toxicité du hIAPP sur les cellules pancréatiques INS-1 du rat.Ayant prouvé la possibilité de moduler le processus d’agrégation de hIAPP par des petits mimes de β-hairpins acycliques portant à la fois des bras peptidiques et peptidomimétiques, nous avons ensuite concentré notre attention sur le développement de β-hairpins fluorés qui, jusqu’à présent, n’ont jamais été explorés ni comme inhibiteurs d’agrégation hIAPP, ni, à notre connaissance, plus largement en chimie médicinale. La préparation de ces analogues fluorés avait le double objectif d’étudier comment le fluor, avec ses caractéristiques uniques, pouvait influencer à la fois l’activité et la conformation de nos inhibiteurs. En conclusion, les travaux présentés dans cette thèse fournissent des informations précieuses pour le développement de nouveaux mimes de β-hairpins acycliques comme modulateurs de hIAPP et potentiellement comme nouveaux outils fluorés pour approfondir son processus d’agrégationType 2 Diabetes (T2D) with over 400 million cases worldwide represents 90% of total diabetes cases. T2D is a degenerative disease associated with insulin resistance and pancreatic β-cells death linked to deposits of the amyloid protein hIAPP (also called amylin), that are observed in the pancreas of over 95% of the T2D patients. The treatments currently available are symptomatic and characterized either by significant side effects or low impact on the incidence of related pathologies and mortality reduction. Thus, to find an etiological treatment for T2D, targeting hIAPP has become a promising strategy to explore. To date, few classes of compounds have been proposed to inhibit hIAPP aggregation process. However, to the best of our knowledge, only very scarce examples of acyclic β-hairpin have been described. Since hIAPP aggregation is a highly complex and dynamic process, we hypothesized that flexible β-hairpins could better adapt to different hIAPP conformations formed during the aggregation process. Our design was based on flexible piperidine pyrrolidine β-turn inducers linked to two different arms inspired by the primary sequence of hIAPP peptide, with a peptidic self-recognition element (SRE) derived from the hIAPP amyloidogenic sequence facing to a peptidic or peptidomimetic blocking sequence. In order to confirm β-hairpin conformation of our inhibitors, our compounds were conformationally studied by NMR and in few cases by molecular dynamics. Then, their ability to interfere with hIAPP aggregation process was primarily evaluated by thioflavin-T fluorescence spectroscopy. The most promising compounds of the series were then investigated by other biophysical assays such as transmission electron microscopy (TEM), capillary electrophoresis (CE) and IMS-MS. The best compounds of the series were then studied to determine their ability to reduce hIAPP toxicity on rat INS-1 pancreatic cells.Having proved the possibility to modulate hIAPP aggregation process employing small acyclic β-hairpin mimics bearing both peptidic and peptidomimetic arms, we then focused our attention on the development of fluorinated hairpin peptidomimetics that, until now, have never been explored either as hIAPP aggregation inhibitors, nor, to our knowledge, more broadly in medicinal chemistry. The preparation of these fluorinated analogues had the double scope to investigate how fluorine, with its unique characteristics, could influence both the activity and the conformations of our inhibitors. In conclusion, the work presented in this thesis provides valuable insight for the development of new acyclic β-hairpin mimics as modulators of hIAPP and potentially new fluorinated tools to further investigate its aggregation process
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Laudet, Béatrice. "Stratégies pour inhiber une interaction protéine-protéine de haute affinité : l'exemple de la protéine kinase CK2." Grenoble 1, 2007. http://www.theses.fr/2007GRE10172.
Full textAbstract:
Les nombreux arguments qui plaident en faveur du potentiel oncogénique de la protéine kinase CK2 en font une cible thérapeutique prometteuse en cancérologie. Cette protéine kinase se présente sous la forme d'un complexe de deux sous-unités catalytiques CK2α constitutivement actives et d'un dimère de sous-unités régulatrices CK2ß. Notre laboratoire a montré que l'interaction dynamique entre ces sous-unités dans la cellule est une composante essentielle dans la régulation de cette enzyme. Pour mieux comprendre cette régulation dans les processus cellulaires normaux et pathologiques, il apparaît nécessaire de développer des molécules capables de perturber cette interaction protéine-protéine. Pour cela, trois stratégies complémentaires ont été utilisées : 1) caractérisation des « hot spots » de l'interaction CK2α- CK2ß à partir de la structure cristallographique du tétramère ; 2) conception rationnelle du premier ligand antagoniste de cette interaction sous la forme d'un peptide cyclique mimétique (IC50 = 3 μM) ; 3) définition à partir de ce peptide d'un pharmacophore utilisable pour identifier des molécules chimiques analogues par une approche de criblage virtuel. Un cluster de molécules inhibitrices actives in vitro et in vivo a ainsi été identifié. Elles représentent les premiers inhibiteurs chimiques de cette interactionMany arguments in favour of oncogenic potential of CK2 protein kinase make it a promising therapeutic target in oncology. This protein kinase is composed of a tetrameric complex of two catalytic subunits CK2a constitutively active and a dimmer of two regulatory subunits CK2b. Our laboratory showed that dynamic interaction between these two subunits in cell is an essential component for this enzyme regulation. For better understanding this regulation in normal and pathologic processes, it seems necessary to develop compounds able to perturb this proteinprotein interaction. In this respect, three complementary strategies were used: 1) hot spots characterization for CK2a-CK2b interaction based on tetramer crystal structure. 2) rational conception of the first antagonist of this interaction as a mimetic cyclic peptide (IC50 = 3 mM). 3) pharmacophore definition based on this peptide allowing to identify chemical molecules analogs by virtual screening. A cluster of chemical compounds active as well in vitro as in vivo has been identified. They represent the first inhibitors for this interaction
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Chorell, Erik. "Pilicides and Curlicides : Design, synthesis, and evaluation of novel antibacterial agents targeting bacterial virulence." Doctoral thesis, Umeå universitet, Kemiska institutionen, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-37161.
Full textAbstract:
New strategies are needed to counter the growing problem of bacterial resistance to antibiotics. One such strategy is to design compounds that target bacterial virulence, which could work separately or in concert with conventional bacteriostatic or bactericidal antibiotics. Pilicides are a class of compounds based on a ring-fused 2-pyridone scaffold that target bacterial virulence by blocking the chaperone/usher pathway in E. coli and thereby inhibit the assembly of pili. This thesis describes the design, synthesis, and biological evaluation of compounds based on the pilicide scaffold with the goal of improving the pilicides and expanding their utility. Synthetic pathways have been developed to enable the introduction of substituents at the C-2 position of the pilicide scaffold. Biological evaluation of these compounds demonstrated that some C-2 substituents give rise to significant increases in potency. X-ray crystallography was used to elucidate the structural basis of this improved biological activity. Furthermore, improved methods for the preparation of oxygen-analogues and C-7 substituted derivatives of the pilicide scaffold have been developed. These new methods were used in combination with existing strategies to decorate the pilicide scaffold as part of a multivariate design approach to improve the pilicides and generate structure activity relationships (SARs). Fluorescent pilicides were prepared using a strategy where selected substituents were replaced with fluorophores having similar physicochemical properties as the original substituents. Many of the synthesized fluorescent compounds displayed potent pilicide activities and can thus be used to study the complex interactions between pilicide and bacteria. For example, when E. coli was treated with fluorescent pilicides, it was found that the compounds were not uniformly distributed throughout the bacterial population, suggesting that the compounds are primarily associated to bacteria with specific properties. Finally, by studying compounds designed to inhibit the aggregation of Aβ, it was found that some compounds based on the pilicide scaffold inhibit the formation of the functional bacterial amyloid fibers known as curli; these compounds are referred to as 'curlicides'. Some of the curlicides also prevent the formation of pili and thus exhibit dual pilicide-curlicide activity. The potential utility of such 'dual-action' compounds was highlighted by a study of one of the more potent dual pilicide-curlicides in a murine UTI model were the compound was found to significantly attenuate virulence in vivo.
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Schumann, Nicholas. "Inhibition of serine and cysteine proteases by peptidomimetic inhibitors." Thesis, 2017. http://hdl.handle.net/2440/126464.
Full textAbstract:
Proteases are responsible for the hydrolysis of proteins and peptides and have been implicated in the development of various diseases. Herein describes the design and synthesis of reversible peptidomimetic inhibitors of serine and cysteine protease for the control of protease activity. Proteases recognise substrates’ secondary peptide structure which conforms to a saw-tooth arrangement of amino acids, known as an extended β-strand geometry. This property has led to the development of potent inhibitors which mimic this conformation. Chapter two discusses defining β-strand geometry in inhibitors, while maintaining key substituents necessary for recognition by protease hosts, by the replacement of N-terminal residues with heterocyclic constraints. The inclusion of a heterocycle both enforces backbone β-strand conformation while increasing inhibitor bioavailability and metabolic stability. A series of peptidomimetic inhibitors containing heterocycles, including pyrrole, furan, thiophene and pyridine were synthesised, and the associated inhibitory activities against a model serine protease, α-Chymotrypsin, determined in proteolytic assays. Of the series of heterocycles, pyrrole was determined to be the optimum heterocycle for inclusion in inhibitors of this class. Extension of this concept of constraint was investigated in the approach towards heterocycle-containing macrocycles constructed by ring-closing metathesis for the inhibition of cysteine Cathepsin proteases, where the introduction of a macrocyclic tether couples with the heterocyclic constraint to define the desired backbone β-strand geometry. Pyrrole-containing macrocycle 2.47 was constructed by ring-closing metathesis, but was found to be unstable to hydrogenation conditions. A similar pyridine-containing macrocycle 2.61 was successfully synthesised and hydrogenated, but was unable to be functionalised with appropriate C-terminal residues due to its poor solubility profile. Chapter three details the design and synthesis of a series of peptidomimetic inhibitors of the serine protease Hip1 which has been implicated with a host innate immune response pathway of Mycobacterium tuberculosis. Described is the synthesis of a library of tripeptides containing an electrophilic boronic ester at the C-terminus for reversible covalent attachment to the Hip1 active site and the associated inhibitory assay data. A lead compound, 3.23, which has exceptional potency of inhibition (low nM activity) was discovered, from which highly potent derivatives featuring a C-terminal aldehyde 3.44, α-keto heterocycle 3.49, and α-keto ester 3.58 were established. Further refinement of these inhibitors presents an opportunity for the development of therapeutics for the treatment of tuberculosis.Thesis (MPhil) -- University of Adelaide, School of Physical Sciences, 2018
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廖笳因. "Synthesis and Pharmacological Evaluation of Amino Acid-Derived and Peptidomimetic γ-secretase Inhibitors." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/60287417370818761229.
Full textAbstract:
碩士國防醫學院
藥學研究所
92
The activity of γ-secretase controls the amount of amyloid β-peptide (Aβ) formation, which is central in the pathogenesis of Alzheimer’s disease (AD). γ-Secretase has been considered central to understanding the etiology of AD because it determines the proportion of the highly fibrillogenic Aβ42 peptide. The fact that Aβ42 is increase in all forms of early-onset AD is very intriguing because this form of Aβ fibrils is toxic to cultured neurons. Therefore, γ-secretase has been one of the major goals of drug discovery for AD. In this study, we started the development of potential γ-secretase inhibitors based on two lead compounds (i) Boc-FΨF-Leu-Val-OMe, a peptidomimetic with hydroxyethyl moiety mimicking the transition-state of aspartyl protease catalysis, (ii) 3,5-difluorophenylacetyl- alanyl-(S)-phenylglycine t-butyl ester (DAPT), an amino acid derivative. Moieties on P1’ and P3’ positions of Boc-FΨF-Leu-Val-OMe and difluorophenylacetyl and alanyl groups of DAPT were the focus of the series of chemical optimizations, respectively. An assay that expresses a Gal4-VP16 (GVP) tagged APP or C99 and a Gal4-promoter luciferase reporter gene were established to monitor the inhibitory potencies for the series of compounds against γ-secretase activity. The results indicated that hydroxyethylureas 23c, 23d, 23e, 23f, 24a, 24b and 24c and amino acid derivative 47 possess the similar or higher activity as compared with Compound E, whereas compounds derived from modification of difluorophenylacetyl and alanyl groups at DAPT dramatically decreased the inhibitory potency against γ-secretase.
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Tsai, Chung-Wel, and 蔡宗衛. "Synthesis of a novel Small Molecular Weight Peptidomimetic non-competitive Inhibitors of Protein Tyrosine Phosphatase 1B." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/73055337364414493765.
Full textAbstract:
碩士國立中央大學
化學研究所
92
ABSTRACT There is evidence that type II diabetes has a connection with insulin resistance. Protein tyrosine phosphatase 1B(PTP 1B) attenuates insulin signal transduction by catalyzing the dephosphorylation of the insulin receptors(IR) and is thus a vital target of potenyial drugs for treatment of type II diabetes. A peptidomimetic sequence targeting at the binding site on PTP1B combined with a suicide inhibition function is the central concept of our design of potential PTP1B inhibitors. A mini library of 5,6-Dihydro-pyran-2-ones was synthesized by a highly efficient scheme which is applicable both in solution-phase synthesis and solid-phase combinatorial synthesis. C-C single bond formation by a stereoselective carbonyl addition gives well-defined stereochemistry in our skeleton and ring closing metathasis(RCM) was applied to afford the dihydropyranone lactone.
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"Profiling of substrate-specificity and rational design of peptidomimetic inhibitors for 3C-like proteases of coronaviruses." Thesis, 2010. http://library.cuhk.edu.hk/record=b6075034.
Full textAbstract:
3C-like protease (3CLpro) of severe acute respiratory syndrome-coronavirus (SARS-CoV) is required for autoprocessing of the polyproteins 1a and 1ab, and is a potential target for treating coronaviral infection. To obtain a thorough understanding of its substrate preference, we created a substrate library of 19 x 8 variants by performing saturation mutagenesis on the autocleavage sequence at P5 to P3' positions. The substrate sequences were inserted between cyan and yellow fluorescent proteins so that the cleavage rates were monitored by in vitro fluorescence resonance energy transfer (FRET). The relative cleavage rate for different substrate sequences was correlated with various structural properties. P5 and P3 positions prefer residues with high beta-sheet propensity P4 prefers small hydrophobic residues: P2 prefers hydrophobic residues without beta-branch. Gln is the best residue at P1 position, but observable cleavage can be detected with His and Met substitutions. P1' position prefers small residues, while P2' and P3' positions have no strong preference on residue substitutions. Noteworthy, solvent exposed sites such as P5, P3 and P3' positions favour positively charged residues over negatively charged one, suggesting that electrostatic interactions may play a role in catalysis. A super-active substrate, which combined the preferred residues at P5 to P1 positions, was found to have 2.8 fold higher activity than the wild-type sequence.Inhibition of SARS-CoV 3CLpro proteolytic activity suppresses virion replication and virus-induced cytopathic effects. Peptidomimetic inhibitors with nitrile warheads, which inhibit Cys protease activity, have been applied for clinical therapy. To investigate whether the nitrile group can target 3CLpro, a series of nitrile-based peptidomimetic inhibitors with various protective groups, peptide length and peptide sequences were synthesized. Inhibitor potency in terms of IC50 and Ki values was determined by FRET assay. Most of these nitrile-based inhibitors in micromolar range can significantly reduce 3CLpro activity. The most potent inhibitor is the tetrapeptidomimetie inhibitor linked with carbobenzyloxy (cbz) group 'cbz-AVLQ-CN' with IC50 and Ki values of 5.9 +/- 0.6 muM and 0.62 +/- 0.11 muM respectively. Crystal structures of 3CLpro-inhibitor complexes demonstrated that nitrite warhead covalently bonded to Cys145, while P1 -- P4 residues interacted with 3CLpro as substrate bound. The cbz group in 'cbz-AVLQ-CN' flipped into a cavity of Gu166 -- Pro168, providing an extra binding force to enhance inhibitor potency. In conclusion, the nitrile-based peptidomimetic inhibitor with cbz group is a convincing model for drug development.
Substrate specificities of various 3CLpro were further investigated by using the substrate library of SARS-CoV 3CLpro. Among various viral strains, the proteases of HCoV-NL63, HCoV-OC43 and infectious bronchitis virus (IBV) were selected from group I, IIa and III respectively for specificity profiling. Their proteolytic rates against 19 x 8 variants were obtained by FRET assay, and correlated with structural properties of substituting residues. Like SARS-CoV 3CLpro in group IIb, these 3CLpro consistently prefer small hydrophobic P4 residues, positively charged P3 residues, hydrophobic P2 residues without beta-branch, P1-Gln and small P1' residues. These proteases also tend to accommodate P5 and P3' residues with positive charge, and P2' residues with small size. In contrast, their preferences on secondary structure are diverse. Correlation was found between IBV 3Clpro activity and beta-sheet propensity at P5 position, while no strong correlation with secondary structure propensities was observed in HCoV-NL63 and HCoV-0C43. Collectively, all 3CLpro share universal preferences on charge, side chain volume and hydrophobicity, but not secondary structure. Their relative activities against universal and specific super-active substrates were elevated to 1.4 -- 4.3, showing synergetic effects by combining preferred residues. These substrates were examined by group I HCoV-229E and group IIa HCoV-HKU1 in parallel. Their activities were highly comparable to those of other group members.
Chuck, Chi Pang.
Adviser: Chi-Cheong Wan.
Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: .
Thesis (Ph.D.)--Chinese University of Hong Kong, 2010.
Includes bibliographical references (leaves [179]-187).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
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Tsai, Chung-Wel, and 蔡宗衛. "Synthesis of a novel Small Molecular Weight Peptidomimetic non-competitive Inhibitors of Protein Tyrosine Phosphatase 1B." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/67424465239606829495.
Full textAbstract:
碩士國立中央大學
化學研究所
92
ABSTRACT There is evidence that type II diabetes has a connection with insulin resistance. Protein tyrosine phosphatase 1B(PTP 1B) attenuates insulin signal transduction by catalyzing the dephosphorylation of the insulin receptors(IR) and is thus a vital target of potenyial drugs for treatment of type II diabetes. A peptidomimetic sequence targeting at the binding site on PTP1B combined with a suicide inhibition function is the central concept of our design of potential PTP1B inhibitors. A mini library of 5,6-Dihydro-pyran-2-ones was synthesized by a highly efficient scheme which is applicable both in solution-phase synthesis and solid-phase combinatorial synthesis. C-C single bond formation by a stereoselective carbonyl addition gives well-defined stereochemistry in our skeleton and ring closing metathasis(RCM) was applied to afford the dihydropyranone lactone.
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Verissimo, Edite. "New approaches to antimalarial chemotherapy: design and synthesis of bicyclic endoperoxides and of peptide and peptidomimetic carbonyl containing cysteine protease inhibitors." Doctoral thesis, 2007. http://hdl.handle.net/10400.1/665.
Full text
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Su, Chi-ting, and 蘇祺婷. "Peptidomimetic Study on the Rice Coleoptile Protease Inhibitor." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/20573470369709105429.
Full textAbstract:
碩士國立成功大學
化學系碩博士班
96
A cyclized peptide from sunflower seeds consists of 14 amino acids and a disulfide bond had been isolated and shown a promising activity as a serine protease inhibitor (SFTI). Therefore, in order to investigate whether a oligomer peptide with a disulfide bond possess potent protease inhibition activity, we have designed a 14-mer peptide, AFCNKMNPPTCRMD, based on the domiam III of rice coleoptile protease inhibitor (RTCI) from 79th amino acid to 92nd amino acid including the proposed active site of the 83rd lysine. This linear peptide was oxidized using known method, followed by purification by employing HPLC gave a compound, the IR spectrum of which showed there were extra absorptions between 600~620 cm-1(-S-S- stretching) and 570~705 cm-1 (-C-S- stretching) compared with that of linear peptide, indicating there was a disulfide bond. The linear and the disulfide bond cyclized peptides were assayed against trypsin and chymotrypsin. It was found that the Kis for cyclized and linear peptides against trypsin with L-BAPNA as substrate are 6.82 x 10-7 and 8.65 x 10-7, respectively. The inhibitory behavior of both showed they are competitive inhibitors. Compared with RTCI (Ki = 4.00 x 10-7) and SFTI (Ki = 5.00 x 10-8), these two peptides are not as active as both when against trypsin. However, when against chymotrypsin with BTEE as substrate, the Kis were 3.08 x 10-8 and 8.06 x 10-8 for cyclized and linear peptides, respectively. Compared with the reported activity for most protease inhibitors, the Ki of which were in the range of 10-8��10-10, our results showed that the disulfide bond cyclized peptide is a promising protease inhibitor. It is thus interesting to further study whether the proposed lysine residue is important in this peptide.
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Marečková, Lucie. "Sekretované aspartátové proteázy kvasinky Candida parapsilosis." Master's thesis, 2012. http://www.nusl.cz/ntk/nusl-310213.
Full textAbstract:
Candida parapsilosis is an opportunistic fungal pathogen of humans causing a variety of infections. Immunocompromised individuals represent the most threatened group of patients. The increasing frequency of infections and occurrence of drug resistant strains are the main reasons for research focused on novel antimycotic compounds. Inhibition of secreted aspartic proteases (Sap) of pathogenic Candida spp. appears to be a potential target of therapeutic intervention. The genome of C. parapsilosis contains at least three genes coding for secreted aspartic proteases, denominated SAPP1-3. Protease Sapp1p has been well biochemically and structurally characterized, whereas Sapp2p and Sapp3p have been given less attention. The first part of the thesis is focused on structural analysis of Sapp1p complexes with selected peptidomimetic inhibitors binding to the active site of the enzyme. In addition, complex of the isoenzyme Sapp2p with the well-known secreted aspartate inhibitor Pepstatin A has been analyzed. The second part is related to the fact that C. parapsilosis belongs to the Candida spp. with the unique ability to translate standard leucine CUG codon mostly as serine. Even though it is a non-conservative substitution of hydrophobic amino acids for a hydrophilic one, this unique ability is maintained for more...
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Brahm, Kevin. "Untersuchung von Peptidomimetika als Inhibitoren für das Chemokin CXCL8." Phd thesis, 2020. https://tuprints.ulb.tu-darmstadt.de/11794/1/Kevin%20Brahm_Dissertation_2020.pdf.
Full textAbstract:
Als kleine Signalmoleküle des Immunsystems spielen Chemokine eine essentielle Rolle bei einer Vielzahl von chronisch entzündlichen Krankheiten und Autoimmunerkrankungen. Die Inhibition der Wechselwirkung dieser Moleküle mit ihren korrespondierenden Rezeptoren ist daher eine wichtige Strategie in der Entwicklung neuer Pharmazeutika zur Therapie dieser Entzündungserkrankungen. Ein Ansatz zur Chemokininhibition sind Peptide, die von diesen Rezeptoren abgeleitet werden und damit die Protein-Rezeptor-Wechselwirkung nachahmen und inhibieren können.
In vorangeganenen Arbeiten wurde mit Hilfe von molekularem Modeling ein Peptid entwickelt, das einen Teil der Bindungsstelle des CXCL8 Rezeptors CXCR1 nachahmt. Dieses Peptid, IL8RPLoops, besteht aus zwei verknüpften Sequenzen aus der zweiten und dritten extrazellulären Schleife der Rezeptors, die ausreichend lang sind, um jeweils eine helikale Windung auszubilden. Es bindet mit submikromolarer Affinität an das Chemokin CXCL8. Wir vermuteten, dass die Vororientierung dieses Peptids in Lösung zu einer Rezeptor-ähnlichen Konformation für die relativ hohe Bindungsaffinität des linearen Peptids verantwortlich ist. Weitere Untersuchungen ergaben, dass am C-terminalen Ende des Peptids Glutaminsäure, statt Glutamin inkorporiert wurde und dieser durch Desamidierung hervorgerufene Austausch die Ausbildung sekundärer Strukturen des freien Peptids begünstigte.
Im ersten Teil dieser Arbeit wurde daher die Auswirkung bestimmter Sekundärstrukturelemente des aus CXCR1 abgeleiteten Peptids auf seine Affinität untersucht. Durch Austausch von helixbildenden Peptidbausteinen mit helixbrechenden Peptoidbausteinen mit gleichen Seitenketten wurde deren Einfluss auf die Struktur des potentiell vororientierten IL8RPLoopsE Peptids untersucht und mit der Auswirkung analoger Austausche an einem unstrukturierten Peptid verglichen, das aus dem N-Terminus des gleichen Rezeptors abgeleitet wurde und damit den anderen Teil der Bindungsstelle nachahmt. Bei Varianten des von vornherein unstrukturierten Peptids führten die helixbrechenden Reste zu einer Abschwächung der Bindungsaffinität, während helixbrechende Reste des IL8RPLoops Peptids diese vollständig verloren. Im CD-Spektrum dieser Varianten waren keine alpha-helikalen Anteile erkennbar. Es wurden MD-Simulationen durchgeführt, um Voraussagen über die Vororientierung der IL8RPLoops Derivate zu treffen. Dabei zeigte sich, dass die Termini von IL8RPLoopsE im Vergleich zu IL8RPLoopsQ sehr nah beieinander liegen und über Wasserstoffbrücken miteinander wechselwirken, so dass ein nicht-kovalenter Zyklus in Lösung vorliegt. Um den Einfluss dieser zyklischen Konformation auf die Bindungseigenschaften der beiden Peptide zu untersuchen, wurden diese durch orthogonale side-chain-to-tail Makrozyklisierung modifiziert. Die kovalente Zyklisierung erhöhte die Affinität des bindenden, linearen Peptids nur leicht, während die vorher nicht-bindende Variante nach Zyklisierung nun fast die gleiche Affinität aufwies. Beide zyklisierten Peptide zeigten in Fluoreszenzanisotropie-Messungen eine hohe Anisotropie, die bei Bindung an CXCL8 sank. MD-Simulationen wiesen darauf hin, dass der Fluorophor, der an einem flexiblen Linker verknüpft war, mit dem Peptid-Makrozyklus interagierte und bei Bindung des Peptids an das Chemokin verdrängt wurde. Die daraus resultierende Beweglichkeit des Fluorophors führt zu niedriger Fluoreszenzanisotropie, ein Effekt der als „Propeller-Effekt“ bekannt ist. Die Makrozyklisierung der Peptide hatte außerdem im Vergleich zu den linearen Varianten eine Erhöhung der Stabilität gegenüber proteolytischem Abbau zur Folge.
Im zweiten Teil der Arbeit sollten Peptidomimetika aus kombinatorischen Bibliotheken identifiziert und weiterentwickelt werden. Die Mix-and-Split Synthese ist eine Strategie, um schnell und einfach eine große und diverse Anzahl von Substanzen zu synthetisieren, die bindende und inhibierende Eigenschaften gegenüber einem Zielprotein aufweisen können. Das Screening einer solchen One-bead-one-compound (OBOC) Bibliothek ist nicht trivial und häufig mit kostspieligen Strategien und Gerätschaften verbunden. Es wurden daher in dieser Arbeit eine Methode, basierend auf zwei-Kanal-Fluoreszenzmikroskopie und eine Methode basierend auf modifizierten Magnetpartikeln validiert, die ein einfaches und kostengünstiges Screening dieser Substanzbibliotheken ermöglichen können. Zur Methodenentwicklung wurde eine Auswahl an Streptavidin bindenden Peptiden auf TentaGel-HMBA-Syntheseharzsynthetisiert und am Harz entschützt. Diese Peptide deckten ein weites Spektrum von Bindungsaffinitäten, als auch andere physikochemische Eigenschaften, wie Nettoladung und Länge der bindenden Sequenz, ab, um eine Aussage über die Anwendbarkeit und Mindestaffinität für die Detektion beider Verfahren treffen zu können. Im fluoreszenzbasierten Verfahren wurden diese Peptide mit fluoreszent-markiertem Streptavidin inkubiert und mit kurzer Belichtungszeit im RHO und FITC-Kanal des Fluoreszenzmikroskops fotografiert, um das Photobleaching zu minimieren. Sekundäre Wechselwirkungen durch elektrostatische Interaktion der mit Peptiden funktionalisierten Partikel und des fluoreszenzmarkierten Proteins wurden durch Variation des Farbstoffs und Kontrollpartikel ausgeschlossen.
Die resultierende Methode ist dafür geeignet, kurze Sequenzen, die im niedrigen mikromolaren Bereich an das Zielprotein binden, zu identifizieren. Sie wurde in nachfolgenden Arbeiten dafür verwendet eine Bibliothek von linearen Peptoid-Hexameren erfolgreich gegen CXCL8 zu screenen und im Anschluss daran 17 Hits zu identifizieren und zu charakterisieren. Im Magnetpartikel-basierten Verfahren wurde die gleiche Auswahl von immobilisierten Peptiden mit Streptavidin-beschichteten Magnetpartikeln behandelt, wobei die Partikel der Biotin-Positivkontrolle und der am stärksten bindende Sequenz ausreichend mit Magnetpartikeln beladen werden konnten, um im Magnetfeld eines Handmagneten mobilisiert zu werden. Es konnte außerdem gezeigt werden, dass die Streptavidin-Magnetpartikel mit biotinyliertem CXCL8 beladen und anschließend zur Abtrennung von CXCR1 transfizierte HEK293-Zellen aus einer Suspension und neutrophilen Granulozyten aus Vollblut verwendet werden können. Schließlich wurde eine OBOC-Bibliothek aus 100 000 verschiedenen makrozyklisierten pentameren Peptoiden synthetisiert und mit Hilfe des magnetpartikelbasierten Verfahrens 22 CXCL8 bindende Partikel aus dieser isoliert. Die Sequenzierung und Charakterisierung dieser Liganden ist Bestandteil nachfolgender Arbeiten. Da die Makrozyklisierung in dieser Arbeit bereits bei CXCL8 bindenden Peptiden zu einer Erhöhung der konformationellen Rigidität und Bindungsaffinität geführt hatte, wurde diese Strategie auch auf die linearen Hexapaptoide aus dem Screening mit 2-Kanal Fluoreszenzmikroskopie angewandt. Es wurde eine on-bead Makrozyklisierung und Fluoreszenzmarkierung dieser 17 Peptoide über zwei zusätzlich am C-Terminus eingeführte orthogonal geschützte Lysinreste durchgeführt. Die resultierenden TAMRA-markierten makrozyklischen Peptomere zeigten ebenfalls den oben beschriebenen „Propeller-Effekt“, und es konnte eine Erhöhung der Bindungsaffinitäten zu CXCL8 um etwa eine Größenordnung im Vergleich zu den entsprechenden linearen Sequenzen nachgewiesen werden.
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Formicola, Lucia [Verfasser]. "Design of peptidomimetics towards new foldamers and 26S proteasome inhibitors / vorgelegt von Lucia Formicola." 2008. http://d-nb.info/1002663032/34.
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Milosevich, Natalia. "Design and synthesis of inhibitors targeting methyllysine reader proteins belonging to the polycomb paralog family." Thesis, 2019. http://hdl.handle.net/1828/10913.
Full textAbstract:
Methyl reader proteins recognize and bind to post-translationally methylated
residues and have functional roles in diverse cellular processes including gene regulation,
development and oncogenesis. The CBX polycomb paralog family of methyllysine
readers recognize trimethyllysine lysine residues on histone tail 3 and repress
transcription by compacting chromatin. The polycomb paralogs form multi-protein
complexes that silence the expression of tumour suppressor genes, and play important
roles in regulating cell cycle and differentiation. Each paralog is structurally similar, yet
has distinct functions, of which many are unknown.
My work has focused on the design and synthesis of CBX inhibitors and on the
development of new methodologies for the discovery of inhibitors targeting methyllysine
readers. In this work, I report on a series of potent peptidic inhibitors that selectively
target the CBX polycombs, as well as the first selective inhibitor for the family member
CBX6, and dual-active inhibitors that target CBX6/CBX8. The results demonstrate the
potential to achieve selectivity through interactions outside of the methyllysine binding
domain. Structural determinants in the binding pocket of each protein that differ within
the family and give rise to selectivity were discovered. I will also report on a series of
peptidomimetic CBX inhibitors that are active in cells. Cellular active inhibitors are
critical for understanding the biological role of each CBX protein and their potential as
therapeutic targets.
New high-throughput approaches are needed to efficiently target methyllysine
readers by chemical inhibition. I describe in this work a strategy for creating massive
libraries of phage-displayed peptidic inhibitors containing methyllysine mimics.
Synthetic optimization on cysteine-containing peptide phage constructs allowed for the
successful installation of Kme3 mimics. This is the first report of a post-translational
methylated peptide phage library. The methodology I developed can be used in a
synthetic chemistry-driven adaptation of traditional phage display for the screening of
millions of peptide-based compounds. Strategies that allow for diversity and high
throughput screening will aid in future efforts in targeting the highly similar CBX
proteins.Graduate
2021-06-01