GlycoNet Investigator Dr. David Vocadlo is leading groundbreaking research unraveling the mysteries of a cellular process vital for maintaining overall cell health. The research team’s recent breakthrough towards understanding how certain proteins are modified by a sugar called N-acetylglucosamine (O-GlcNAc) has revealed a key factor at play—a specific amino acid sequence. This finding opens up new paths for researchers to explore and could help spur the development of new drugs and therapies for neurodegenerative diseases and cancer.

The complexity of this cellular process, known as O-GlcNAcylation, has presented challenges that illustrate the need for a collaborative approach to explore its functions and regulation. The protein O-GlcNAc Transferase (OGT) installs O-GlcNAc onto over a thousand proteins within cells, safeguarding their health and function. However, a key challenge within the field has been discerning what factors influence how OGT targets these various proteins. 

“We decided to tackle this problem and we developed a collaboration with 48Hour Discovery,” said Dr. Vocadlo, who is a Professor and Tier 1 Canada Research Chair in Chemical Biology at Simon Fraser University.

Collaborating with 48Hour Discovery was a key catalyst, enabling Dr. Vocadlo’s team to search the company’s extensive peptide libraries – these peptides (or chains of amino acids) are similar to proteins, but shorter. Dr. Vocadlo’s lab worked with a team of scientists led by Dr. Ratmir Derda, another GlycoNet Investigator and the Founder of 48Hour Discovery. Together, they harnessed 48Hour’s proprietary drug discovery technology to search for peptides with the potential to interact with OGT protein, the key regulator of O-GlcNAc in cells. 

Through rigorous testing, the researchers uncovered a specific peptide sequence with an important role. This sequence acts as a code, directing peptides to attach to OGT, which influences its behaviour. The groundbreaking revelation is a major stride forward, suggesting novel methods to control OGT and regulate the inner workings of our cells. 

“We think that understanding how OGT binds and is regulated within the cell will allow us to inhibit its activity on certain sets of proteins, and that may be beneficial,” said Dr. Vocadlo.

The significance of this research is far-reaching, opening up new possibilities, both in terms of understanding cell physiology and the development of targeted therapies. These findings have the potential to be exploited to create new strategies and targeted therapies to combat various neurodegenerative diseases and cancers.

“This has been a fantastic collaboration,” concluded Dr. Vocadlo. “We believe these findings will stimulate others to explore the mechanisms regulating O-GlcNAc, and hope the work will open the door to advancing OGT as a therapeutic target.”

More information about this research and access to the recently published scientific paper can be found on the Proceedings of the National Academy of Sciences website. [https://www.pnas.org/doi/epdf/10.1073/pnas.2303690120]