A5086475676- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Synthesis and Catalytic Reactions
- RNA and protein synthesis mechanisms
- Advanced biosensing and bioanalysis techniques
- Peptidase Inhibition and Analysis
- Cyclopropane Reaction Mechanisms
- Protein Degradation and Inhibitors
- Viral Infections and Immunology Research
- Monoclonal and Polyclonal Antibodies Research
- Biochemical and Structural Characterization
- Cyclization and Aryne Chemistry
- CRISPR and Genetic Engineering
- Catalytic Alkyne Reactions
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Gout, Hyperuricemia, Uric Acid
- interferon and immune responses
- Cellular transport and secretion
- Catalytic C–H Functionalization Methods
- Amino Acid Enzymes and Metabolism
- Bacteriophages and microbial interactions
- Retinal Development and Disorders
- Trace Elements in Health
- Heat shock proteins research
University of California, San Francisco
2022-2024
Imperial College London
2016-2022
University of Leeds
2021-2022
Molecular Sciences Institute
2018-2020
Queen Mary University of London
2018
Transnational Press London
2018
Abstract The uric acid/xanthine H + symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans . Here we present crystal structure of genetically stabilized version UapA (UapA-G411V Δ1–11 ) in complex with xanthine. formed two domains, core domain and gate domain, similar to previously solved uracil UraA, which belongs same family. shows an inward-facing conformation xanthine bound residues domain. Unlike was observed be monomer, forms dimer...
Abstract Cysteine‐reactive small molecules are used as chemical probes of biological systems and medicines. Identifying high‐quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan‐reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine‐reactive based upon the maximization selectivity, is described. This was applied prospectively discover fragments that target clinically important cell cycle...
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein factors have been hampered by excessive toxicity. Here we describe KZR-8445, a cyclic depsipeptide that targets Sec61 translocon and selectively disrupts secretory membrane in signal peptide-dependent manner. KZR-8445 potently inhibits secretion pro-inflammatory cytokines primary immune cells highly efficacious mouse model rheumatoid arthritis. A cryogenic...
The development of electrophilic ligands that rapidly modify specific lysine residues remains a major challenge. Salicylaldehyde-based inhibitors have been reported to form stable imine adducts with the catalytic protein kinases. However, targeted in these examples is buried hydrophobic environment. A key unanswered question whether this strategy can be applied on surface protein, where rapid hydrolysis resulting salicylaldimine more likely. Here, we describe series aminomethyl-substituted...
Novel intramolecular hydride transfer onto arynes is exploited in a redox-neutral intermolecular α-functionalization of amines with diverse pronucleophiles.
Abstract Nucleophilic amino acids are important in covalent drug development yet underutilized as anti-microbial targets. Chemoproteomic technologies have been developed to mine chemically accessible residues via their intrinsic reactivity towards electrophilic probes but cannot discern which reactive sites contribute protein function and should therefore be prioritized for discovery. To address this, we a CRISPR-based oligo recombineering (CORe) platform support the rapid identification,...
Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines sulfonimidamides, far less studied have yet to be applied field of bioconjugation. Herein, we report a range different synthetic methodologies constructing sulfoximine sulfonimidamide architectures that allows access new areas chemical space. We demonstrate how late-stage functionalization can these motifs...
Chemical probes that covalently modify cysteine residues in a protein-specific manner are valuable tools for biological investigations. Covalent fragments increasingly implemented as probe starting points, but the complex relationship between fragment structure and binding kinetics makes covalent optimization uniquely challenging. We describe new technique discovery enables data-driven of potency selectivity. This platform extends beyond existing repertoire methods identifying hits by...
RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these exhibit a similar fold and contain an essential catalytic cysteine, offering opportunity inhibit enzymes with electrophilic small molecules. Here we describe successful application quantitative irreversible tethering (qIT) identify acrylamide fragments that target active site cysteine 3C protease (3Cpro) Enterovirus 71, causative agent hand, foot mouth...
Preventing the biogenesis of disease-relevant proteins is an attractive therapeutic strategy, but attempts to target essential protein factors have been hampered by excessive toxicity. Here, we describe KZR-8445, a cyclic depsipeptide that targets Sec61 translocon and selectively disrupts secretory membrane in signal peptide-dependent manner. KZR-8445 potently inhibits secretion proinflammatory cytokines primary immune cells highly efficacious mouse model rheumatoid arthritis. A cryo-EM...
Abstract Cysteine‐reactive small molecules are used as chemical probes of biological systems and medicines. Identifying high‐quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan‐reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine‐reactive based upon the maximization selectivity, is described. This was applied prospectively discover fragments that target clinically important cell cycle...
A novel Rab27A construct enables elucidation of covalent ligand binding, paving the way for structure-guided approaches against this challenging target.
A novel strategy for the synthesis of vinyl sulfonamide fragments application to irreversible protein tethering.
Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines sulfonimidamides, far less studied have yet to be applied field of bioconjugation. Herein, we report a range different synthetic methodologies constructing sulfoximine sulfonimidamide architectures that allows access new areas chemical space. We demonstrate how late stage functionalization can these motifs...
Small molecules that react to form covalent bonds with proteins are widely used as biological tools and therapeutic agents. Screening cysteine-reactive fragments against a protein target is an efficient way identify chemical starting points for probe development. Mass spectrometry often the site degree of fragment binding. However, robust hit identification requires characterization kinetics binding can be readily achieved using quantitative irreversible tethering. This screening platform...
ABSTRACT RNA viruses are critically dependent upon virally encoded proteases that cleave the viral polyproteins into functional mature proteins. Many of these structurally conserved with an essential catalytic cysteine and this offers opportunity to irreversibly inhibit enzymes electrophilic small molecules. Here we describe successful application quantitative irreversible tethering (qIT) identify acrylamide fragments selectively target active site 3C protease (3C pro ) Enterovirus 71,...
The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, its abnormal activation leads to cancers through fusions or point mutations. Mutations that disrupt the disulfide network extracellular domain (ECD) of drive multiple endocrine neoplasia type 2A (MEN2A), hereditary syndrome associated with development thyroid cancers. However, structural details how specific mutations affect are unclear. Here, we present first insights into ECD...
Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines sulfonimidamides, far less studied have yet to be applied field of bioconjugation. Herein, we report a range different synthetic methodologies constructing sulfoximine sulfonimidamide architectures that allows access new areas chemical space. We demonstrate how late stage functionalization can these motifs...