Global ETD Search
Search theses and dissertations gathered from participating repositories worldwide. Every result links back to the library that holds it. No account is needed.
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Showing 1 to 20 of 20 for “"stapled peptides"”.
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Development of stapled peptides targeting the Ral GTPases
… oncogenic Ras signalling. Prior work identified stapled peptides based on the Ral effector, RLIP76, that can bind to the Ral GTPases and disrupt downstream signalling. To improve the affinity of these peptide sequences, an affinity maturation was performed on the Ral-binding domain of RLIP76 from …
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Strain-promoted Stapled Peptides for Inhibiting Protein-protein Interactions
… double-click cycloadditions with diazidopeptides to generate stapled peptides that are capable of inhibiting PPIs. However, the Sondheimer dialkyne suffers from poor water-solubility; it decomposes rapidly in aqueous solutions which limits its application in biological systems. This …
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Towards Inhibition of Oncogenic RhoA Signaling using Stapled Peptides
… simulations on a series of all-hydrocarbon stapled peptides identified two staples - a C-terminal i,i+4 on 60-64 residues (L4) and a central i,i+7 staple on 53-60 positions (L7) - that were the most likely to stabilise α-helical conformations conducive to RhoA binding. Biophysical assays …
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The development of stapled peptides as chemical tools to investigate activin A signalling and as antibacterial agents targeting MsbA-mediated efflux
Peptides are recognised for their ability to disrupt protein-protein interactions (PPIs), which have traditionally been considered ‘undruggable’ with small molecules. However, due to issues such as a susceptibility to degradation by proteases, the use of peptide therapeutics in the clinic has been …
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The development of functionalised stapled peptides as chemical tools to modulate biological processes in platelets and as novel antimicrobial therapeutics targeting Pseudomonas aeruginosa
Peptides are useful modulators of protein-protein interactions (PPIs) and cellular membranes, both of which are traditionally challenging to target using small molecules. Often therapeutic peptides suffer from issues including poor proteolytic stability. Two-component peptide stapling can improve …
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CYCLIZATION-BASED SITE-SELECTIVE N-TERMINAL CYSTEINE CONJUGATION, PEPTIDE STAPLING AND HISTONE DEACETYLASE (HDAC) PROBING
… modify N-terminal cysteines of unprotected peptides or proteins in a single step. We showed that α-fluoroketone molecules afford the cyclization reaction with the beta amino thiol group of N-terminal cysteine. Both chemo and stereo-selectivity of this reaction have been studied using 2D NMR …
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Design and synthesis of molecular tools for the ubiquitin proteasome system
… for peptide stapling, an initial palette of nine peptides, containing the wild-type E2-25K sequence, and eight stapled analogues, were successfully synthesized and ring-closed on the solid phase. Circular dichroism spectroscopy was used to analyse secondary structure, revealing the peptides …
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Development of stapled peptide targeted covalent inhibitors and synthesis of novel ADC payloads for applications in cancer therapy
… in cancer therapeutics. 1) Development of stapled peptide–targeted covalent inhibitors (SPTCIs) of p53–MDM2 protein–protein interaction (PPI). Herein, the development and synthesis of three novel electrophilic staples and four stapled peptides are described. The stapled peptides bear …
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Proteolysis targeting chimeras for the directed ubiquitination of the androgen receptor
… of prostate cancer. First, in this work stapled peptide PROTACs recruiting E3 ligase MDM2 for AR degradation were investigated. MDM2 has been underexploited as an E3 ligase for PROTACs, despite a beneficial ability to modulate the p53 protein, a vital tumour suppressor, in additional to …
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Tandem mass spectrometry approaches to characterizing challenging biomolecules : stapled and cyclic peptides and variants of lipid A from gram-negative bacteria
… complex biomolecules. Specifically, cyclic and stapled peptides have become an intriguing class of biomolecules in drug research afforded to them because of their biological stability and resistance to proteolytic digestions. However, challenges are presented in regards to the characterization …
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The structure of human pro-myostatin and molecular basis of latency
… I present preliminary data on prodomain derived stapled peptides as inhibitors of myostatin signalling.
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Interrogation and engineering of RAD51:BRC repeat interactions
… for cysteine stapling of recombinantly produced peptides was optimised to yield the correct product of high purity. The optimised stapling methodology provides a promising general approach for recombinant production and evaluation of cysteine-stapled peptides. Peptides were rationally designed in …
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One-Carbon Bridge Stapling for use in Peptide-Drug Conjugates
… Conjugates Bethany M. Cooper Therapeutic peptides lie in between small molecules and therapeutic proteins in terms of their molecular weight and have many advantageous properties, such as high potency and selectivity. Yet one fundamental shortcoming of therapeutic peptides is their poor …
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Second-site inhibitors of the estrogen and androgen hormone receptors
… the synthesis of a library of hydrocarbon ‘stapled’ peptides that target the androgen receptor coactivator binding groove. This class of alpha-helix-stabilized peptides has shown efficacy in mouse models, and demonstrates decreased rates of proteolytic degradation and increased cellular …
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Development of new catalytic transformations and reagents for the construction of C-N and C-S bonds
… Lastly, new types of bio-therapeutics - stapled peptides and linker-free antibody-drug conjugates - could be synthesized using the new method.
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DEVELOPMENT OF NEW PEPTIDE-BASED NANOMATERIALS AS POTENTIAL TOOLS FOR CRYOPRESERVATION OF TISSUES AND ORGANS
… AFP primary sequence through the synthesis of peptides or lastly, increasing the antifreeze activity through the exploitation of a multimeric approach, taking advantage from self-assembly processes or the simultaneous presentation of several ice binding motifs, that allows to reduce the …
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Organometallic Palladium Reagents for Polypeptide Bioconjugation and Macrocyclization
Chapter 1: Bicyclic peptides have been developed to mimic good binders that structurally resemble antibody mimetics. The identity of the linker plays a critical role in enforcing the structure of the cyclic entity. Palladium-mediated arylation has enabled cysteine-specific modifications with a …
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Approaches Towards the Inhibition of Anti-Apoptotic Proteins
… twenty-two conformationally-constrained peptides were generated to target the protein-protein interaction (PPI) of CK2 and affect its function. The lead peptide, P7-F1C5, presented a novel, highly-functionalised constraint that allowed the molecule to become cell-permeable, exert its …
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Developing Constrained p27 Peptides to Target the Oncogenic E3 Ubiquitin Ligase SCF-Skp2
… this PPI. We have designed and synthesised p27 peptides containing unnatural amino acids and successfully constrained them using ‘click’ chemistry. The dissociation constants show that the constrained peptides (CPs) have dramatically higher affinities for the Cks1-Skp2- Skp1 complex compared …
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Small Molecules and Their Conjugates with Peptides: Chemical Strategies to Tackle Resistant Bacteria
Antimicrobial resistance is an increasingly important issue as it renders currently used antibiotics ineffective. There are different approaches how to slow down emergence of resistance, including better stewardship of the current treatments, release of drugs in a more selective way, or discovery …