A New Way to Target “Undruggable” Proteins

Harvard University researchers have developed a nanobody-based tool that can remove sugars from proteins, i.e., glycosylate or deglycosylate proteins, without off-target effects. Published in Nature Chemical Biology last month, the new tool allows researchers to study the effect of sugars on protein function, potentially revealing ways to target “undruggable” proteins involved in chronic diseases. 

Though people think of sugar mostly as something sweet to eat, sugar, or glycans, serve several biological functions, from helping to shuttle proteins between cells to ensuring proper protein function through post-translational modifications, such as glycosylation. Through these functions, glycans are involved in inflammation and disease, such as in diabetes or cancer.

The majority of proteins currently cannot be targeted by drugs, however, controlling which glycans are present on proteins could be one way to do so. Until now, researchers had no way to study the effects of sugars on protein function, as there was no way to target glycosylation or deglycosylation to a specific protein of interest.

In this study, researchers focused on O-linked N-acetylglucosamine (O-GlcNAc), a post-translational modification found on thousands of “undruggable” proteins. They fused O-GlcNAcase, an enzyme that can perform deglycosylation, to a nanobody—a novel type of antibody fragment much smaller than traditional antibodies, in order to selectively target the fused O-GlcNAcase enzyme to a specific protein. By changing the nanobody, the tool can target different proteins for deglycosylation by O-GlcNAcase.

Using this tool, researchers were able to selectively remove O-GlcNAc from two transcription factors, demonstrating that this may be a new way to control gene function. Though, the researchers are unsure whether the nanobody itself may interfere with the function of target proteins. Some labs have already used the new tool to study how O-GlcNAc affects proteins in an animal model of neurodegenerative disease. 

The researchers hope that by understanding the effect of glycans on proteins, they’ll be able to design new drugs to target “undruggable” proteins to treat chronic diseases, such as cancer, diabetes, and Alzheimer’s.