A5066837290- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- Biochemical and Molecular Research
- Tryptophan and brain disorders
- Peroxisome Proliferator-Activated Receptors
- Immune Cell Function and Interaction
- Metabolism and Genetic Disorders
- Click Chemistry and Applications
- Cancer-related gene regulation
- Bioactive Compounds and Antitumor Agents
- Enzyme Structure and Function
- Cancer therapeutics and mechanisms
- Peptidase Inhibition and Analysis
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Protein Degradation and Inhibitors
- Ubiquitin and proteasome pathways
- Antibiotic Resistance in Bacteria
- Medical Imaging Techniques and Applications
- Amino Acid Enzymes and Metabolism
- Cancer, Hypoxia, and Metabolism
- Escherichia coli research studies
- Vibrio bacteria research studies
- Carbohydrate Chemistry and Synthesis
- Catalytic C–H Functionalization Methods
Immunocore (United Kingdom)
2020-2023
Genomics England
2016-2020
University of Oxford
2015-2020
Genomics (United Kingdom)
2015-2019
GlaxoSmithKline (United Kingdom)
2015-2017
University of Dundee
2012-2015
University of St Andrews
2005-2007
Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that irreversibly bind target overcome the low affinity limits reversible fragment screening, but such electrophilic were considered nonselective rarely screened. We hypothesized mild electrophiles might selectivity challenge constructed a library 993 mildly fragments. characterized this by new high-throughput thiol-reactivity assay screened...
Abstract New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand breaks. Here we report first co-crystal structures antibacterial QPT-1 and anticancer drug etoposide with Staphylococcus aureus gyrase, showing binding at same sites in cleaved as fluoroquinolone moxifloxacin. Unlike moxifloxacin, interact conserved GyrB TOPRIM residues rationalizing why...
Protein secretion systems are critical to bacterial virulence and interactions with other organisms. The Type VI system (T6SS) is found in many species used target either eukaryotic cells or competitor bacteria. However, T6SS-secreted proteins have proven surprisingly elusive. Here, we identified two secreted substrates of the antibacterial T6SS from opportunistic human pathogen, Serratia marcescens. Ssp1 Ssp2, both encoded within gene cluster, were confirmed as toxins delivered by T6SS....
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind Fe(II) in active site. Substitution from C4 pyrazole moiety allows access peptide substrate binding site; incorporation conformationally constrained 4-phenylpiperidine linker gives such as 54j...
A paucity of novel acting antibacterials is in development to treat the rising threat antimicrobial resistance, particularly Gram-negative hospital pathogens, which has led renewed efforts antibiotic drug discovery. Fluoroquinolones are broad-spectrum that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility been compromised resistance. We have identified a class antibacterial thiophenes with unique mechanism action and activity against range bacterial...
Synaptic vesicle protein 2A (SV2A) is a ubiquitous component of synaptic vesicles (SVs). It has roles in both SV trafficking and neurotransmitter release. We demonstrate that Casein kinase 1 family members, including isoforms Tau–tubulin kinases (TTBK1 TTBK2), phosphorylate human SV2A at two constellations residues, namely Cluster-1 (Ser42, Ser45, Ser47) Cluster-2 (Ser80, Ser81, Thr84). These residues are also phosphorylated vivo , the phosphorylation Thr84 within essential for triggering...
Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions natural TCRs (e.g., immune-mobilizing monoclonal receptors [ImmTAC]...
Modifications of histone tails, including lysine/arginine methylation, provide the basis a "chromatin or code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader was identified as putative oncogene transcriptional coactivator. Here we report SPIN1 chemical probe inhibitor with low nanomolar in vitro activity,...
Mucosal-associated invariant T (MAIT) cells use canonical semi-invariant cell receptors (TCR) to recognize microbial riboflavin precursors displayed by the antigen-presenting molecule MR1. The extent of MAIT TCR crossreactivity toward physiological, microbially unrelated antigens remains underexplored. We describe TCRs endowed with MR1-dependent reactivity tumor and healthy in absence metabolites. bearing crossreactive self are rare but commonly found within donors display T-helper-like...
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library 600,000 fragments into high-resolution structure KDM4A. Among most interesting chemotypes were 5-aminosalicylates, which two distinct but...
Some Gram-negative bacteria target their competitors by exploiting the type VI secretion system to extrude toxic effector proteins. To prevent self-harm, these also produce highly specific immunity proteins that neutralize antagonistic effectors. Here, peptidoglycan endopeptidase specificity of two secretion-system-associated effectors from Serratia marcescens is characterized. These small secreted proteins, Ssp1 and Ssp2, cleave between γ-D-glutamic acid L- meso -diaminopimelic with...
The nonpolymorphic class Ib molecule, HLA-E, primarily presents peptides from HLA Ia leader peptides, providing an inhibitory signal to NK cells via CD94/NKG2 interactions. Although of pathogenic origin can also be presented by HLA-E T cells, the molecular basis underpinning their role in antigen surveillance is largely unknown. Here, we solved a co-complex crystal structure TCR with peptide (pHLA-E) bacterial (Mycobacterium tuberculosis) origin, and first TCR-pHLA-E complex noncanonically...
Abstract Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role several biological processes. Achieving selectivity over different KDMs has been major challenge for KDM inhibitor development. Here we report potent selective KDM5 covalent inhibitors designed to target cysteine residues only present sub‐family. The binding targeted proteins was confirmed by MS time‐dependent inhibition. Additional competition assays show that...
Fluoroquinolone drugs such as moxifloxacin kill bacteria by stabilizing the normally transient double-stranded DNA breaks created bacterial type IIA topoisomerases. Previous crystal structures of Staphylococcus aureus gyrase with asymmetric DNAs have had static disorder (with duplex observed in two orientations related pseudo-twofold axis complex). Here, 20-base-pair homoduplexes were used to obtain crystals covalent DNA-cleavage complexes S. gyrase. Crystals QPT-1, or etoposide diffracted...
Abstract Covalent probes can display unmatched potency, selectivity and duration of action, however, their discovery is challenging. In principle, fragments that irreversibly bind target overcome the low affinity limits reversible fragment screening. Such electrophilic were considered non-selective rarely screened. We hypothesized mild electrophiles might challenge, constructed a library 993 mildly fragments. characterized this by new high-throughput thiol-reactivity assay screened them...
Residues in the histone substrate binding sites that differ between KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences order improve affinity for KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 V313 (KDM4A numbering) targeted. Additionally, conformational restriction of flexible pyridopyrimidinone C8-substituent investigated. These approaches...
Tryptophan is an important precursor for chemical entities that ultimately support the biosynthesis of key metabolites. The second stage tryptophan catabolism catalysed by kynurenine formamidase, enzyme different between eukaryotes and prokaryotes. In present study, we characterize catalytic properties crystal structures three bacterial formamidases. reveal a new amidase protein fold, highly organized distinctive binuclear Zn2+ centre in confined, hydrophobic relatively rigid active site....
Combined photochemical arylation, "nuisance effect" (SN Ar) reaction sequences have been employed in the design of small arrays for immediate deployment medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out control" terms selectivity; example ortho-arylation 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SN Ar processes. As a result, number crystallographic hits against NUDT7, key peroxisomal...
Abstract Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role several biological processes. Achieving selectivity over different KDMs has been major challenge for KDM inhibitor development. Here we report potent selective KDM5 covalent inhibitors designed to target cysteine residues only present sub‐family. The binding targeted proteins was confirmed by MS time‐dependent inhibition. Additional competition assays show that...
Abstract Introduction: Presentation of dysregulated or neoantigen peptides by human leukocyte antigens (pHLA) are a key source novel targets for cancer immunotherapy. ImmTAC molecules class T cell redirecting bispecific fusion protein that utilize an affinity enhanced TCR to target tumor selective pHLA. Tebentafusp, our lead clinical candidate, is molecule gp100-derived peptide presented HLA-A*02:01. The aim this study was investigate whether the gp100 could be other HLA alleles (i.e....