Increasing evidence suggests the endolysosomal system represents a means of targeting multiple disease mechanisms. Endolysosomal transport can be enhanced by improving the function of the Retromer pathway. The retromer complex, composed of an apparent three-protein core, is a trafficking machinery within the endolysosomal system that regulates cargo sorting to maintain cellular homeostasis. Using current structural knowledge of the Retromer complex, in silico small molecule binding screening was performed. Small molecules of interest were selected and tested for their biophysical binding to the Retromer complex. Protein levels were assessed in vitro. The binding of the small molecules and its effect on the Retromer complex could have therapeutic potential in Retromer-related neurodegenerative disease such as Alzheimer’s Disease.
Proteins are like essential workers in our bodies, enabling all our actions. How these proteins move around is crucial. If this movement is disrupted, it can lead to cell damage, especially in our brains, causing various problems. Recent research suggests that when a protein transportation system called retromer doesn’t work correctly, it can contribute to neurodegenerative diseases like Alzheimer’s Disease.
To tackle this issue, we used the known structures of retromer proteins to search for small molecules that can bind to the retromer proteins. We tested these molecules both in biophysical assays and in cellular models. When the retromer proteins are bound by the molecules, retromer becomes more stable and perform their job better, potentially leading to new therapies for various disease, for example, Alzheimer’s disease.