David Vocadlo



Key Research Areas
Associated Researchers
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Recent Research Projects

Canada Research Chair in Chemical Glycobiology

2014/15-2020/21 • $1,400,000 • PI
Over half of human proteins have sugar units attached to them and hundreds of genes are dedicated to processing specialized sugars. Cells respond to changes in their surroundings by changing the sugar structures present on their surface - enabling specialized cells to regulate many processes in...

Streptococcus pneumoniae glycan-processing enzymes: understanding and targeting their roles in virulence

2018/19-2020/21 • $884,177 • PI,CO
Streptococcus pneumonia (the pneumococcus) is a bacterium that often lives in the nose and throats of humans. This relationship is most often benign but this microorganism is also an accomplished disease-causing germ that can cause mild ailments, such as earaches, to lethal illnesses like...

Understanding the link between peptidoglycan recycling and beta-lactam antibiotic resistance in Gram negative bacteria

2016/17-2020/21 • $738,513 • PI,CO
The efficacy of beta-lactam antibiotics is being eroded by the increasing prevalence of bacteria that produce AmpC beta-lactamase, an enzyme that inactivates most clinically available beta-lactams. AmpC is produced by many pathogenic Gram negative bacteria including Pseudomonas aeruginosa, a...

Glycosylation of hydroxymethylcytosine in mammalian genomes - distribution and functional roles.

2016/17-2020/21 • $723,668 • PI,CO
Proteins are expressed from the genes contained within the DNA of our chromosomes. The regulation of gene expression in humans controls a wide range of processes, spanning from cellular growth and development through to wound healing and adaptation to variations in diet. Inappropriate regulation...

Regulation of proteostasis by glycosylation of nucleocytoplasmic proteins.

2018/19-2020/21 • $493,956 • PI,CO
The cells of all organisms need to adapt to changes in their environment. One mechanism enabling adaptation to environmental changes, including variation in nutrient availability and cellular stressors such as heat, is the ability of cells to tune their levels of specific proteins. This process,...

Regulation of Hipk protein kinases by nutrient sensing mechanisms

2018/19-2020/21 • $420,337 • PI,CO
We study "Hipk" proteins and their regulation of cell and organ growth. Hipks are found in many species including humans and fruit flies. Research in flies provides a powerful and rapid way to use genetics to manipulate development and cellular growth. We generated a new type of fly strain that...

Single turnover covalent chaperones for disease related lysosomal enzymes

2020/21 • $135,151 • PI,CO
Parkinson's disease (PD) is a worldwide health problem that has been linked to deficiencies in an enzyme called glucocerebrosidase (GCase). This enzyme plays a critical role in the body by breaking down a particular large molecule into two smaller, more easily metabolized components, a sugar...

CRISPR-Cas9 genome-wide pooled screen for the identification of unknown glucocerebrosidase modulators

2020/21 • $45,000 • Scholarship/Fellowship,Other
Parkinson's disease (PD) is the second most common neurodegenerative disease, yet remarkably, no therapy exists that can slow the disease. The increasing incidence of PD makes improving our knowledge of the mechanisms and factors leading to PD of importance. Mutations in the gene GBA, which...

Chemical biology tools for studying carbohydrate processing enzymes

2015/16-2019/20 • $445,000 • PI
The modification of proteins with sugars is known as protein glycosylation and is a common modification of cellular proteins in all kingdoms of life. Glycosylation is particularly abundant in multicellular eukaryotes, where over half of all proteins are thought to be modified by sugars linked...

Elucidating the Effect of O-GlcNAc Modification on Protein Thermostability

2016/17-2019/20 • $135,000 • Scholarship/Fellowship,Other
The glycosylation of proteins with O-GlcNAc is a ubiquitous post-translational modification found throughout the metazoans. Deregulation of O-GlcNAcylation is implicated in several human diseases including type II diabetes, Alzheimer's, and cancer. However, the basic biochemical role of...

NSERC CREATE Collaborative Medicinal Chemistry Network in Epigenetics Training (ChemNET):Training Canadian chemists within a global open access public-private partnership

2013/14-2018/19 • $1,554,496 • PI,CO
The proposed CREATE program (Medicinal Chemistry Network in Epigenetics Training; ChemNET) willtrain the next generation of medicinal chemists within an open access, international research collaboration involving four Canadian universities, the Structural Genomics Consortium (SGC) - a...

Structural and Functional Analysis of Pneumococcal Carbohydrate-Processing Pathways.

2013/14-2018/19 • $1,071,346 • PI,CO
Understanding the structure and function of proteins has served to illuminate their critical functions in diverse organisms. Here we focus on a family of related enzymes from the Streptococcus pneumonia (the pneumococcus), which is a bacterium that often lives in the nose and throats of humans....

Operations and Maintenance Support: UBC Regional Structural Biology Facility

2016/17-2017/18 • $300,000 • PI,CO
Structural biology is a branch of the Life Sciences that seeks to provide atomic-level descriptions of the three-dimensional structures of biological molecules, including proteins, DNA, RNA and sugars. This structural information is critical for understanding the diverse functions of these...

Generation of effective carbohydrate-based inhibitors of a glycosidase implicated in Alzheimer disease and their molecular mechanism of action.

2012/13-2016/17 • $528,667 • PI
Alzheimer disease (AD) manifests both by the development of extracellular amyloid deposits (plaques) and intracellular aggregates known as neurofibrillary tangles (NFTs). The plaques result from accumulation of an insoluble peptide known as amyloid beta (Abeta). The NFTs arise from a form of the...

An Automated Synthesis Platform to Support Drug Discovery and Reaction Development

2016/17 • $150,000 • PI,CO
Rapid parallel synthesis, especially in conjunction with screening of chemical fragments (fragment-based drug discovery), is a mainstay of modern medicinal chemistry and allows for rapid production of multiple analogs of a lead or hit structure, in parallel reactions. A single chemist, utilizing...

A super-resolution microscope for visualizing cellular structure and dynamics

2016/17 • $150,000 • PI,CO
Well below the resolution limit dictated by the wavelength of light, super-resolution confocal microscopes bend the laws of physics to allow cell and developmental biologist to peer down at molecular machines at work within living cells. This Nobel prize winning advance in microscopy is quickly...

Regulation of cellular proteostasis by glycosylation of nucleocytoplasmic proteins.

2016/17 • $100,000 • PI,CO
The ubiquitous modification of cellular proteins with a specialized sugar known as O-GlcNAc is found in all multicellular organisms. O-GlcNAc is attached to over a thousand proteins and has been shown to be involved in cellular processes ranging from controlling the expression of genes to...

Supercritical Fluid Chromatography Instrumentation for Chiral Organic Molecule Analysis

2015/16 • $149,894 • PI,CO
Organic molecules play a central role in many biological processes, from signaling molecules used by insects, to the development of the next generation of drugs for human diseases. To study these compounds effectively, scientists must be able to separate individual molecules from the complex...

The role of the O-GlcNAc post-translational protein modification in epigenetic regulation of gene expression

2010/11-2014/15 • $1,172,695 • PI,CO
Proper functioning of an enzyme called OGT, which puts a simple sugar residue on various proteins, has been implicated in insulin signaling, neurodegenerative diseases, and cellular stress response. We recently found that OGT regulates the turning on and off of certain genes, with potential...

Overcoming Antibiotic Resistance: Targeting the AmpC beta-lactamase induction pathway

2010/11-2014/15 • $609,399 • PI,CO
Our most safe and effective antibiotics are the Beta-lactams; however, the protection they offer against infection is being eroded by the increasing prevalence of bacterial pathogens expressing AmpC beta-lactamase. AmpC is found in many bacteria including Pseudomonas aeruginosa, a significant...

Chemical tools to study eukaryotic protein glycosylation

2010/11-2014/15 • $450,000 • PI
Glycoconjugates are key biomolecular structures within organisms that are composed of several different interlinked sugar units, most commonly attached to either lipids or proteins. The allocation of approximately 300 genes within the human genome to the proper stepwise assembly and disassembly...

Chemical biology approaches to understanding glycosylation mediated gene silencing

2012/13-2014/15 • $135,000 • Scholarship/Fellowship,Other
How genes are regulated within cells defines how they become different during development of an organism and, in turn, give rise to different tissues. These differences between cells occur despite all cells encoding the same genome and the differences that develop can be passed on from cells to...

Role of O-GlcNAc glycosylation in protein stability

2012/13-2014/15 • $135,000 • Scholarship/Fellowship,Other
Keeping proteins stable and functional is a crucial aspect of the cell health especially when cells are placed under certain forms of stress. Several mechanisms have been identified within cells that act to verify that proteins are properly assembled, appropriately stable, and are shuttled...

Chemical tools to study eukaryotic protein glycosylation

2010/11-2014/15 • $120,000 • PI
No summary

Research Grant for 2011 EWR Steacie Memorial Fellowship Successful Candidate

2011/12-2013/14 • $1,500,000 • Scholarship/Fellowship
No summary

Canada Research Chair in Chemical Glycobiology

2010/11-2013/14 • $400,000 • PI
No summary

CD Spectrophotometer for Biological Studies

2013/14 • $148,351 • PI,CO
This proposal aims to solicit funds so that researchers at Simon Fraser University can replace a currentlyout-dated and semi-functional "CD Spectrophotometer" with a top-quality research instrument. In order to understand chemical and biochemical binding interactions, which are very important in...

Degradation of host glycans in the lung by Streptococcus pneumoniae.

2010/11-2012/13 • $608,106 • PI,CO
The major causative agent of acute respiratory disease, pneumonia, is Streptococcus pneumoniae (pneumococcus). In roughly ~40% of humans this bacterium is a transient commensal of the throat and upper respiratory tract. However, S. pneumonia frequently slips out of this passive role and into one...

UV-visible Spectrophotometer

2012/13 • $65,827 • PI,CO
This proposal aims to solicit funds so that researchers at Simon Fraser University can replace a currently non-functional "UV-vis Spectrophotometer" with a top-quality research instrument. In order to understand chemical and biochemical reactions it is necessary to measure the rate of reaction,...

Equipment for chemical glycobiology

2010/11 • $113,628 • PI
No summary

Patents

Selective glycosidase inhibitors, methods of making inhibitors, and uses thereof

The invention comprises compounds for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions containing the compounds or prodrugs of the compounds. The invention also comprises animal models and methods of making the animal models for studying diseases and disorders related to deficiency or overexpression of O-GIcNAcase, accumulation or deficiency of O-GIcNAc, and treatment of such diseases and disorders. The invention also comprises methods of...
Related applications: CA20062599843, WO2006CA00300, EP20110184538, EP20060705254, CA20062819464

Selective glycosidase inhibitors and uses thereof

The invention provides compounds of formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc.
Related applications: WO2007CA01554, EP20110157096, EP20110157096, EP20070800577, CA20072661582

SELECTIVE GLYCOSIDASE INHIBITORS AND USES THEREOF

The invention provides compounds of Formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds. The invention also provides methods of treating diseases and disorders related to deficiency or overexpression of O-G1cNAcase, accumulation or deficiency of O-G1cNAc.
Related applications: EP20110780012, WO2011CA00548

PYRANO[3,2-D]THIAZOL DERIVATIVES AND USES AS SELECTIVE GLYCOSIDASE INHIBITORS THEREOF

Pyrano[3,2-d]thiazol derivatives of formula (I) for selectively inhibiting glycosidases, prodrugs of the compounds, and pharmaceutical compositions including the compounds or prodrugs of the compounds are provided. Methods of treating diseases and disorders related to deficiency or overexpression of O-GlcNAcase, accumulation or deficiency of O-GlcNAc are also provided.
Related applications: WO2011CN72330