PROJECTS

Transcription factors control the initiation and the rate of transcription; one of the key stages in the coding of DNA to produce proteins. Signal transducers and activators of transcription (STATs) are a group of cytosolic proteins that regulate the transcription of several genes which induce multiple hallmarks of cancer, including uncontrolled cell proliferation and cell immortality.

 

STAT3 and STAT5 have been identified as oncoproteins in numerous human cancers, including breast, blood, and brain tumours. Current efforts seek to create a small-molecule inhibitors of the dimerization event between two STAT proteins.

 
 

Ubiquitination is one of the most understood post-translational modifications, yet the function of ubiquitin-like modifiers (Ubls), and their influence on diverse biological processes, is still poorly understood.

 

Recently, protein labeling with the ubiquitin-fold modifier 1 (UFM1) has been highlighted as a cellular support system due to its role in protecting stressed cells from apoptosis.

 

Our efforts have focused on targeting the E1 activating enzyme UBA5, responsible for priming UFM1, using a structure-based design approach. In addition to targeting UBA5, we are using novel methods to selectively inhibit other E1 activating enzymes. Our goal is to develop new therapies based on the inhibition of Ubl-like pathways.

 

Localization of proteins to specific cellular areas is essential for maintaining their proper levels of activity. Thus, affecting protein localization, rather than its function or levels, can be a viable therapeutic strategy.  

 

We believe that one of the approaches to deactivate non-membrane-bound proteins is to induce their anchorage to cellular membrane structures.   


We are exploring several approaches to accomplish inducible protein immobilization using small molecules and short peptides with both covalent and non-covalent mechanisms of action.  

 

Phosphorylation regulates a vast spectrum of cellular processes. In certain cases, the distance between neighbouring phosphate groups found on the surface of biomolecules can serve as a marker for certain disease states, cell viability, or protein activation. 

 

We are interested in the development of chemosensor-based assays that can probe for proximal phosphorylation to enable the detection of molecules and surfaces associated with diseases states.

 

Additionally, we are employing these chemosensors towards the detection of highly phosphorylated bacterial membranes. This sensing platform is being developed as a rapid method to diagnose bacterial infections in sterile bodily fluids, including blood and CSF.

 

To accomplish both research aims, we are exploring creative approaches to linking phosphate-binding supramolecular complexes with fluorescent and luminescent reporters.

 

 

Development of drug screening technologies goes hand in hand with drug discovery. Demand for more affordable high-throughput screens, as well as screens for new protein targets, is always substantial.  


We combine the findings from our medicinal chemistry and chemosensory projects to arrive at innovative drug-screening platforms. These platforms are optimized for fluorescence and luminescence-based applications in aqueous solutions, on blotting membranes and for cell imaging.

 

 

Histone deacetylases (HDACs) control the rate and abundance of post-translational protein deacetylation, in conjunction with histone acetyltransferases (HATs), which fulfil the antagonistic role.

 

HDACs coordinate the removal of acetyl groups from the ε-amino group of lysines in a wide variety of protein classes, most notably histones; the proteins around which DNA is coiled.

 

Deacetylation of histone lysines enhances the electrostatic interaction that binds the protein with DNA, resulting in a tightly packed chromatin structure. The DNA therefore becomes inaccessible to other proteins such as transcription factors, meaning that HDACs play a pivotal role in controlling gene expression.

 

Previous research has shown that HDACs are overexpressed in multiple aggressive human cancers, e.g. PDAC, and blood-borne malignancies, such as multiple myeloma, making HDACs a key therapeutic cancer target.

 

The Gunning Group seeks to create small-molecule inhibitors capable of inhibiting multiple HDAC isoforms simultaneously, as well as selective HDAC inhibitors, working through a competitive, as well as covalent mode of binding.

 

UNIVERSITY OF TORONTO MISSISSAUGA

GUNNING GROUP © 2019

CONTACT US

  • White LinkedIn Icon
  • White Twitter Icon