Maxwell Miao

• CDT Doctoral Researcher (Aligned) Supervisor: Dr Celina Cano
• Email: D.Miao3@newcastle.ac.uk
• Project title: Design and Synthesis of Allosteric Inhibitors of GALK1

Institution: Newcastle University

Project Summary: Classic galactosemia is a metabolic disorder characterised by the mutation on the gene encoding galactokinase 1 (GALK1), the mutation causes the inability to correctly metabolise galactose and leads to the accumulation of toxic metabolites α-D-galactose-1-phosphate, which can cause symptoms such as edema (swelling of the brain), kidney issues, liver failure and in some extreme cases sepsis. These symptoms can present in newborns and if left untreated can be fatal. The recent study of GALK1 crystal structures identified a novel allosteric binding pocket and developed a series of fragments by x-ray crystallography-based fragment screening. The growth of these fragments and further analysis of the co-crystal structure of fragments bound to GALK1 led to the identification of hit compounds of allosteric inhibitor of GALK1. Through the design and synthesis of further analogues of the hit compound, coupled with biophysical, structural and cellular characterisation, the project aims to develop a sub nM allosteric inhibitor of GALK1.