Small Molecule Rescue of GLUT1DS

GLUT1DS is a disease in the body that affects the human Glucose Transporter 1 protein (hGLUT1), it involves a missense mutation in the SLC2A1 gene and as a result one of the amino acids in the GLUT1 protein is translated incorrectly causing the structure to be misfolded and dysfunctional. GLUT1 transports glucose into the brain and acts as the primary gate of glucose into the brain. It controls the energy of the brain and thus it has a vital role in the function and development of the brain. As a result glucose is unable to be shuttled into through the blood brain barrier and causes a series of energy related failures in the brain of developing infants, paroxysms, reduced development of microvasculature, ataxia, epilepsy, and intellectual disability, GLUT1DS is be a disease that can greatly lower the quality of life of those afflicted. As a result the study aims to find a small molecule that can help address this deficient structure by acting as a structural stabilizer, restoring function, and thus alleviating symptoms. In order to accomplish this, a virtual screening software was used in order to simulate the interactions of molecules with each other. After compiling a library of compounds that could potentially be orally consumed by humans, the software simulated how these compounds would interact with a mutated form of the GLUT1 protein. The simulation showed how well each of the proteins bonded to the ligands, and thus it showed affinity. Then in order to validate this, the ligand that was identified sounded most favorably to the protein was chosen as a candidate. This candidate was a flavonoid known as glycycoumarin

Rather than using GLUT1 a structural homolog found in bacteria known as xylE was used instead. The bacteria were then put into multiple different petri dishes that had a nutrientless agar (attempt 1), and a nutrient rich agar (attempt 2) each was filled with xylose as a source of carbon. A portion of the petri dishes were put under a stressor, such as heat, PH, or under UV light. These stressors acted to simulate the mutations that GLUT1 faces. Then of this portion under stress, glycycoumarin was placed into another portion. Finally by counting how many E coli resided in each dish the effectiveness of the glycycoumarin in fixing the stressed xylE was found. If the amount of stressed dishes with glycycoumarin had a significant increase in the amount of E Coli then it can be said that the glycycoumarin was able to aid the xylE in consuming xylose.

It was found that the glycycoumarin was not able to make a significant difference in the survival of E Coli. The study also lacked rigor and scale meaning that a strong conclusion about glycycoumarin’s effect on GLUT1 or XylE was not proven in this study. However further investigation that more directly explores the interaction between glycycoumarin and GLUT1 without needing to use XylE as a representative of GLUT1 that can directly measure the function of GLUT1 are recommended.