A5004693639- Protein Degradation and Inhibitors
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Multiple Myeloma Research and Treatments
- Antimicrobial Peptides and Activities
- Microbial Natural Products and Biosynthesis
- Probiotics and Fermented Foods
- Epigenetics and DNA Methylation
- Peptidase Inhibition and Analysis
- Biochemical and Structural Characterization
- Cyclization and Aryne Chemistry
- Ubiquitin and proteasome pathways
- CAR-T cell therapy research
- Carbohydrate Chemistry and Synthesis
- Cancer Genomics and Diagnostics
- Biochemical effects in animals
- Catalytic Alkyne Reactions
- Protein Hydrolysis and Bioactive Peptides
- Porphyrin and Phthalocyanine Chemistry
- Oxidative Organic Chemistry Reactions
- Radical Photochemical Reactions
- Synthesis and Reactions of Organic Compounds
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
University of Calgary
2014-2024
Alberta Children's Hospital
2021-2024
Alberta Children's Hospital Research Institute
2024
Children’s Health Research Institute
2023
Institute of Cancer Research
2023
Jamia Millia Islamia
2021
Calgary Laboratory Services
2016-2021
Research Network (United States)
2021
Weill Cornell Medical College in Qatar
2021
Northwest University
2016
Protein–protein interactions (PPIs) have emerged as significant targets for therapeutic development, owing to their critical nature in diverse biological processes. An ideal PPI-based target is the protein myeloid cell leukemia 1 (MCL1), a prosurvival factor cancers such multiple myeloma where MCL1 levels directly correlate disease progression. Current strategies halting antiapoptotic properties of revolve around inhibiting its sequestration proapoptotic factors. Existing inhibitors disrupt...
Current methods for the preparation of heterobifunctional pomalidomide-conjugates rely on that are often low yielding and produce intractable byproducts. Herein we describe our strategy succinct pomalidomide-linkers.
The type IIa bacteriocins are antimicrobial peptides isolated from lactic acid bacteria that act as food preservation agents and have nanomolar activity against pathogens such Listeria monocytogenes. Previous reports with mutant indicate the conserved disulfide bridge between cysteine residues 9 14 in leucocin A (1) is critical for antibiotic properties, which mediated by target membrane receptor proteins belonging to mannose phosphotransferase (mpt) system. To examine whether can be...
Chemical synthesis of lantibiotic analogues wherein monosulfide bridges are replaced with other groups can shed light on structure−activity relationships and generate variants that resistant to aerobic oxidation have better metabolic stability. This work describes the first complete a carbocyclic analogue 2, using sequential on-resin ring-closing olefin metathesis solution-phase peptide synthesis. The methodology described should find wide application for preparation rigidified...
Vascular pathology is increased in diabetes because of reactive-oxygen-species (ROS)-induced endothelial cell damage. We found that vitro and a streptozotocin model vivo, metformin at diabetes-therapeutic concentrations (1-50 µM) protects tissue-intact cultured vascular cells from hyperglycemia/ROS-induced dysfunction typified by reduced agonist-stimulated endothelium-dependent, nitric oxide-mediated vasorelaxation response to muscarinic or proteinase-activated-receptor 2 agonists. Metformin...
Abstract N ‐Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used construct different heterocyclic skeletons by varying the coupling partner. Indolizines formed via an ‐deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2‐Dihydropyrimidines a...
Thiophene-containing porphyrin compounds are capable of catalytic, photo-reductive dehalogenation on an array α-halo ketone model substrates with low catalyst loadings (0.1 mol%), in the presence energy, red light (>645 nm).
Abstract Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who prescription or illicit opioids. Hyperactive autonomic output underlies many the aversive symptoms that make it difficult to discontinue use. The locus coeruleus (LC) an important centre within brain with poorly defined role in withdrawal. We show here pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during Within LC, we found spinally projecting tyrosine...
Gamma delta T cells (γδTc) have tremendous anti-tumoral activity, thus γδTc immunotherapy is currently under development for various malignancies. We targeted breast cancer stem-like (BCSC), a rare cell population responsible patient mortality. BCSC were mostly susceptible to immunotherapy, yet some escaped. The secretome rendered hypo-responsive, and resistant expressed more PD-L1 anti-apoptotic protein MCL-1 than non-stem-like (NSC). resistance was partially overcome by dMCL1-2, an...
Self-renewal is a crucial property of glioblastoma cells that enabled by the choreographed functions chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover axis mediated histone variant macroH2A2. With omics functional assays deploying patient-derived in vitro vivo models, show macroH2A2 shapes accessibility...
Photolysis of the amino acid derived symmetrical and unsymmetrical diacyl peroxides at 254 nm low temperature (−78 to −196 °C) generates various bis(amino acids) in a concise manner with orthogonal protection. The methodology was applied synthesis (4R)-5-propyl-l-leucine (PrLeu), component HUN-7293.
Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not require C4 and C5 positions be functionalized observe regioselectivity. Using method, we completed synthesis a recently reported JAK 1/2 inhibitor. Our produces desired product 4 steps from commercially available starting materials.
High and dry: Three analogues of leucocin A (shown in figure) six pediocin PA-1 were synthesized which conserved cysteines that form a disulfide bond replaced by pairs hydrophobic amino acids. Noncovalent interactions all the LeuA derivatives effectively afforded peptides with full antimicrobial activity. In contrast, Ped inactive except for 5 d.
Synthesis of a chiral cysteine derivative 2 with the carboxyl protected by an acid-labile 4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl (OBO) orthoester is reported. A disulfide anchoring strategy used to link sulfur this OBO onto modified trityl polystyrene resin for synthesis peptides having C-terminal (Cys) residues. Fmoc-based solid phase peptide affords model tripeptides without significant epimerization. The approach make orally active analgesic crotalphine and its Cys1 diastereomer.
A library of novel structural hybrids menthol and cubebol was tested for each derivative's ability to interact with the transient receptor potential subfamily melastatin member 8 (TRPM8) channel. This structure–activity relationship study revealed three potent modulators TRPM8 ion channel: a agonist (4) an EC50 value 11 ± 1 μM, antagonist (15) IC50 2 allosteric modulator (21) that minimized channel desensitization toward menthol. Each these exocyclic olefin analogues is readily accessible by...
Abstract Interaction of (2‐diphenylphosphoryl‐3‐iodo‐4‐methoxy‐phenyl) methanol with NaH in DMF at ambient temperature results the generation benzyne intermediates that can be trapped by furan or DMF. Trapping forms 3‐(dimethylaminomethyl)‐2‐hydroxy‐6‐methoxybenzaldehyde demonstrating simultaneous exchange three functionalities a single step. The presence alkoxy substituent adjacent to iodine is critical for high regioselectivity addition corresponding bromide triflate used place iodide...
The production of several bacteriocins in lactic acid bacteria is regulated by inducer peptide pheromones that specifically interact with their cognate bacterial receptor. These are between 19 and 27 aa long contain a conserved (V/I)-X-X-X-F sequence followed positively charged residues the C-terminal domain. CbaX EntF share similarity involved carnobacteriocin A Carnobacterium maltaromaticum LV17A enterocins B Enterococcus faecium CTC492, respectively. CbaX, two hybrids, : were tested for...
The synthesis of small-molecule linkers for installation thalidomide-based conjugates is described. Linker properties have been recognized as vital to conjugate success in drug discovery and delivery systems. These tethers act linkages between molecules, can also aid cell permeability, solubilizing agents. This work shows our progress synthesizing with a variety linker characteristics. adaptability manipulation these other holds potential improving synthetic control chemical connectivities...
Enantioselective nucleophilic acylation catalysis provides a simple method of determining absolute configuration for unsaturated alcohols. Extension this technique to natural products and synthetic compounds, as well current limitations approach, are also described.
To develop new degrader molecules from an existing protein ligand a linkage vector must be identified and then joined with suitable E3 ligase without disrupting binding to the respective targets. This is typically achieved through empirically evaluating degradation efficacy of series synthetic degraders. Our strategy for determining optimal sites utilises biotinylated ligands, linked via potential conjugation inhibitor confirm whether target maintained after forming conjugate. method...