Developing new molecules that reduce brain and spinal cord swelling after traumatic injury or stroke

Aquaporin channels are plasma membrane proteins that regulate cellular water homeostasis. As a result of the low oxygen conditions from stroke or in response to a traumatic central nervous system (CNS) injury, aquaporin channels increase the cellular influx of water, leading to CNS swelling (oedema). The primary aquaporin in the CNS is AQP4. Thus, AQP4 channel inhibition presents an attractive target for preventing the damage resulting from CNS oedema. All prior efforts focused on direct inhibition of AQP4 function have not resulted in any suitable molecules for human use, mainly due to the lack of verified AQP4 channel binding molecules. The Aston team has identified several structurally related direct AQP4 pore blocking molecules as well as novel ways to inhibit AQP4 function by focusing on reducing the abundance of AQP4 at the brain cell surface. This PhD project will fully characterise these hits and generate new and improved molecules. Validated scaffolds will be further optimized for AQP4 affinity/inhibition and assessed for selectivity and pharmacokinetic properties. Validated scaffolds will provide the basis for the development of molecules to reduce CNS oedema. This project is an exciting new direction for the treatment of devastating CNS injuries and stroke that could provide enormous potential benefit to patient health.