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 18 of 18 for “"covalent inhibitors"”.
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Design and Synthesis of Covalent Inhibitors as Novel Anti-Infective Compounds
… describes approaches to develop selective, covalent inhibitors of enzymes in infectious diseases.<br/><br/> Covalent inhibitors are drugs which are capable of forming a covalent bond to their target. This can give them many advantages over traditional, non-covalent drugs from a …
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Design, Synthesis and Evaluation of Covalent Inhibitors for Tissue Transglutaminase and Factor XIIIa
… towards the discovery of potent and selective covalent inhibitors for each isozyme, namely hTG2 and hFXIIIa. The first project was concentrated on the inhibition of hTG2 activity. Ubiquitously expressed in tissues, hTG2 is a multifunctional enzyme. Its primary activity is the formation of …
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Development of stapled peptide targeted covalent inhibitors and synthesis of novel ADC payloads for applications in cancer therapy
… 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 moieties to covalently target a …
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Development of novel lysine targeting covalent inhibitors for Bruton’s tyrosine kinase and casein kinase 2 and synthesis of novel hybrid androgen receptor inhibitors
… novel class of hybrid compounds designed through covalently linking enzalutamide and EPI-001 through triazole-PEG linkers is reported. The compounds are accessed in 6 synthetic steps performed in parallel for the 5 final target compounds. The compounds display a 50-fold improvement in the cell …
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Towards targeted post-translational modification of endogenous proteins in complex environments
… can be exploited pharmacologically, as covalent inhibitors such as aspirin covalently bind, or attach a covalent payload, to the active sites of enzymes. Following this principle, rationally designed targeted covalent inhibitors (TCIs) adapt non-covalent ligands to react with …
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A Binary Approach for Selective Recognition of Nucleic Acids and Proteins
… The binary approach was also applied to design covalent inhibitors for HIV-1 reverse transcriptase (RT). In this application, two separate pre-reactive groups were attached to a natural RT ligand, deoxythymidine triphosphate (dTTP). Upon binding of both dTTP analogs in the RT active site, the …
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Discovery and optimization of inhibitors and probes that target New Delhi metallo-[beta]-lactamase
… the β-lactam substrate. Codrugs in the form of covalent inhibitors that target this nucleophilic serine are prescribed along β lactam antibiotics to counteract this form of resistance. However, an emerging class of β lactamases, known as metallo-β-lactamases (MBLs), poses a threat to this …
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Designed Bond Cleavage Reactions for Next-Generation Therapeutics
… aims to address the inherent challenges of covalent inhibitors (CIs), which pose risks of off-target effects despite being a significant proportion of small-molecule therapeutics. Chemical moieties, such as the ,-unsaturated system in acrylamides, make it challenging to design a prodrug …
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Investigating the structure-function relationships of Plasmodium Haem Detoxification Protein and Phosphatidylinositol 4-kinase
… on the development of both ATP-competitive and covalent Plasmodium PI4Kβ inhibitors. Two residues of interest in Plasmodium vivax PI4Kβ unique to Plasmodium, F832 and C1327, were mutated to alanine. F832 is thought to form key Pi-Pi interactions with inhibitors and C1327, found on the periphery …
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QUANTITATIVE PROTEOMIC APPROACHES TO STUDY DRUG MECHANISM OF ACTION
In recent years an increased number of covalent protein kinase inhibitors has been approved for cancer therapy and many more are undertaking clinical trials. Covalent binding is usually obtained by introducing in these drugs an electrophilic warhead able to bind specific nucleophilic sites in the …
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Interrogating therapeutic resistance to oncogenic KRASG12C-based therapies in colorectal cancer
… therapeutic target. The recent approval of novel covalent inhibitors selective for KRASG12C mutation have entered the clinic, which has not only marked a major milestone in cancer drug discovery but has also intensified efforts to directly target other KRAS mutations that have also successfully …
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The Development of Assays for Detecting Proximal Phosphorylation and Covalent Modification of Proteins
… modular electrophilic warhead platform for novel covalent inhibitors. Through nucleophilic aromatic substitution methodology, selectively derivatized polyfluorinated benzene rings were synthesized to construct an electrophilic warhead library that could be electronically and sterically tuned for …
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Substituted aryl glycosides as probes of the mechanism of spontaneous ad enzyme-catalyzed glycoside hydrolysis
… the observed rate differences. The role of non-covalent interactions between the enzyme active site and the hydroxyl groups of the substrate glycone in the mechanism of Agrobacterium faecalis r3-glucosidase, as well as the amount of charge generated at the transition states for the enzymic …
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Affinity Maturation of Peptides to Bind Protein-Protein Interfaces
The use of peptides as inhibitors for protein-protein interactions (PPI) is an attractive strategy for developing therapeutics. Understanding the structure-activity relationships of peptide-based inhibitors is crucial for optimizing their activity. To guide this optimization, combinatorial peptide …
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Discovery of covalent modifiers via the complexity to diversity strategy
Targeted covalent drugs have recently become integral parts of drug discovery. Given the advantages of high-throughput screening in drug discovery, many electrophilic fragment collections have been developed as a promising alternative to discover and validate novel targets. However, most covalent …
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Structural examination of trypanosomatid tubulin-binding cofactors and pteridine reductase 1 inhibition
… obtained. These include the discovery of two covalent inhibitors, confirming the reactivity of a non-conserved active site cysteine, and molecules that are able to bind simultaneously at two locations within the active site pocket, exploiting hydrogen-bonding interactions with key catalytic …
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Targeting final steps of sugar nucleotide biosynthetic pathway against <i>Aspergillus fumigatus</i>
… synthesize β-1,3 glucan from UDP-Glc. Although inhibitors of other glycosyltransferases (e.g. chitin synthases) also exhibit antifungal activity, only echinocandins have been approved for the treatment of aspergillosis. This is due to intrinsic drawbacks of targeting glycosyltransferases. …