Computational Chemistry And Structural Biology Approaches To Tackle Huntington's Disease
Huntington’s Disease (HD) is a fatal hereditary neurodegenerative disease caused by expansion of the CAG repeat tract at the 5’ of the huntingtin (htt) gene resulting in polyglutamine expansion of the HTT protein (polyQ-HTT) of aberrant function. HD symptoms include loss of motor coordination, cognitive and speech impairment, and psychiatric disorders. HD affects approximately 1 in 7000 people in Canada, and there are no cures or disease-modifying therapies to date. This project aims to identify heterobifunctional small molecules (PROTACs) meant to revert or halt HD progression by binding E3 ubiquitin ligases and recruiting these to polyQ-HTT species, promoting their ubiquitin-mediated degradation. Atomic structures of polyQ-HTT-proximal E3 ligases will serve as a basis for computer-aided ligand design. Cocrystal structures of in vitro-positive hits, complexed with the E3 ligases, will guide ligand optimization. The project will broaden the applicant’s expertise in structural biology, computational chemistry, and will expand his knowledge in the fields of protein aggregation diseases and protein degradation as a therapeutic strategy; it will also expand SGC’s track record on E3 ligases and polyQ-HTT targeting. The chemical handles for E3 ligases generated will serve the global community working on PROTACs as a novel therapeutic modality.