When scientists say our bodies are complex, I find that a severe understatement. In only a second, so many things happen in our body that it's impossible to comprehend. One extremely essential factor to this efficiency is the production of enzymes in your body, which we rely on for almost every function you can think of. Reactions that would take years in our body’s environment get reduced to small fractions of a second with enzymes. But, what happens when an essential enzyme doesn’t get produced?
Our First Steps
Me and my PhD mentor explored this phenomenon with a genetic disease called Morquio A Syndrome, or Mucopolysaccharidosis IV Type A (MPS IVA). This is a debilitating lysosomal storage disorder caused by mutations in the gene encoding the enzyme GALNS. The mutations lead to the harmful accumulation of glycosaminoglycan substrates that were meant to be broken down by GALNS, particularly keratan sulfate (KS) and chondroitin-6-sulfate (C6S), within the lysosomes. The resulting cellular dysfunction manifests in severe clinical symptoms, including skeletal deformities, corneal clouding, and cardiac issues.
However, there is only a single safe treatment, which is enzyme replacement therapy (ERT). The lack of variability and the hefty cost of treatments for the disease is what inspired the goal of this research; we want to explore a new method of treatment that is almost, if not equivalently as effective as ERT.
The Solution
The focus of my research is to investigate different molecules for their potential to serve as a pharmacological chaperone (PC). PCs are small molecules that can stabilize misfolded proteins, enhancing their proper folding and function. Some studies we reviewed explained that different molecules like ezetimibe, pranlukast, and bromocriptine could dock within the active site of GALNS, mimicking the natural substrates' interaction and potentially aiding in the enzyme's stability.
One of the main drawbacks of this solution is that some molecules bind so strongly to the enzyme that after stabilizing, the molecule stays in the active site of the enzyme and doesn’t allow the substrate to bind. This is where binding affinity and kinetics comes into play. We need to find a molecule that has just the right affinity to the enzyme for stabilizing and also maintaining function and allowing the reaction to be catalyzed (kinetics).
So far, the research has had its ups and downs, and I will be continuing to go further into this topic with a PhD student mentor. We will try to find a promising derivative or variant of a molecule that would be best for binding to the enzyme for stabilization, but also doesn’t bind to the enzyme too strongly.
I'll keep on updating any significant progress made and what the end result of the paper will cover.
Image inspiration: Boyd, R. E., Lee, G., Rybczynski, P., Benjamin, E. R., Khanna, R., Wustman, B. A., & Valenzano, K. J. (2013). Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases. Journal of Medicinal Chemistry, 56(7), 2705–2725. https://doi.org/10.1021/jm301557k
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