A5076963617- Carbohydrate Chemistry and Synthesis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Glycosylation and Glycoproteins Research
- Lysosomal Storage Disorders Research
- Enzyme Production and Characterization
- Trypanosoma species research and implications
- Biochemical and Structural Characterization
- Chemical Synthesis and Analysis
- Enzyme Catalysis and Immobilization
- Cellular transport and secretion
- Pharmacological Effects of Natural Compounds
- Click Chemistry and Applications
- Metal-Catalyzed Oxygenation Mechanisms
- Pancreatic function and diabetes
- Crystallography and molecular interactions
- Fungal Biology and Applications
- Metal complexes synthesis and properties
- Antimicrobial Peptides and Activities
- Pancreatitis Pathology and Treatment
- Natural Antidiabetic Agents Studies
- Microbial Metabolites in Food Biotechnology
- Antifungal resistance and susceptibility
- Peptidase Inhibition and Analysis
- Hemoglobin structure and function
University of British Columbia
2012-2020
Pennsylvania State University
2019-2020
Canada's Michael Smith Genome Sciences Centre
2016-2018
University of Graz
2014
A highly divergent route to lipophilic iminosugars that utilizes the thiol–ene reaction was developed enable rapid synthesis of a collection 16 dideoxyiminoxylitols bearing various different substituents. Enzyme kinetic analyses revealed number these products are potent, low-nanomolar inhibitors human glucocerebrosidase stabilize enzyme thermal denaturation by up 20 K. Cell based assays conducted on Gaucher disease patient derived fibroblasts demonstrated administration compounds can...
The iron-dependent oxidase UndA cleaves one C3-H bond and the C1-C2 of dodecanoic acid to produce 1-undecene CO2. A published X-ray crystal structure showed that has a heme-oxygenase-like fold, thus associating it with structural superfamily includes known postulated non-heme diiron proteins, but revealed only single iron ion in active site. Mechanisms proposed for initiation decarboxylation by cleavage using monoiron cofactor activate O2 necessarily invoked unusual or potentially unfeasible...
Human pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence glucose, and therefore an attractive therapeutic target the treatment of diabetes obesity. Here we report discovery a unique lariat nonapeptide, by means RaPID (Random non-standard Peptides Integrated Discovery) system, composed five amino acids in head-to-side-chain thioether macrocycle further four 310 helical C terminus. This potent inhibitor HPA (Ki = 7 nM) yet exhibits selectivity over...
The alkylating warhead of the pancreatic cancer drug streptozotocin (SZN) contains an N-nitrosourea moiety constructed from Nω-methyl-l-arginine (l-NMA) by multi-domain metalloenzyme SznF. enzyme's central heme-oxygenase-like (HO-like) domain sequentially hydroxylates Nδ and Nω′ l-NMA. Its C-terminal cupin then rearranges triply modified arginine to Nδ-hydroxy-Nω-methyl-Nω-nitroso-l-citrulline, proposed donor functional pharmacophore. Here we show that HO-like SznF can bind Fe(II) use it...
Selective inhibitors of human pancreatic α-amylase (HPA) are an effective means controlling blood sugar levels in the management diabetes. A high-throughput screen marine natural product extracts led to identification a potent (Ki = 10 pM) peptidic HPA inhibitor, helianthamide, from Caribbean sea anemone Stichodactyla helianthus. Active helianthamide was produced Escherichia coli via secretion as barnase fusion protein. X-ray crystallographic analysis complex with porcine revealed that...
De novo macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique unexpected solutions to challenging biological problems. This is due in part their unusual folds, which are able side chains ways not available canonical structures α-helices β-sheets. Despite much recent interest these molecules, folding binding behavior remains poorly characterized. In this work, we cocrystallization, docking, solution NMR of three de peptides that all bind...
Simplified analogues of montbretin A bind similarly to human alpha amylase and with nanomolar affinity.
Helianthamide is a potent inhibitor of human pancreatic α-amylase (HPA) (KI = 0.01 nM) produced by the Caribbean sea anemone Stichodactyla helianthus. was previously shown to be structurally homologous β-defensins and represents new structural class protein inhibitors α-amylase. To understand source this inhibition, we performed site-directed mutagenesis studies on helianthamide fusion proteins. A novel YIYH inhibitory motif that interacts with conserved active site residues originally...
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series new cyclopentanoid β-galactosidase were prepared and their inhibitory chaperoning activities determined compared with those lipophilic analogs the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships investigated by X-ray crystallography well alterations in cyclopentane moiety such deoxygenation replacement fluorine...
Abstract Pathogenic fungi kill an estimated 1.3 million people each year. This number is predicted to rise as drug resistance spreads, thus antifungal drugs with novel modes of action are urgently required. Fungal endoglycoceramidase‐related proteins 1 and 2 (EGCrP‐1 ‐2), which hydrolyse glucosylceramide ergosteryl β‐glucoside, respectively, important for fungal cell growth have been identified potential targets development. A library iminosugar derivatives was screened against EGCrP‐1 ‐2, a...