PROTEIN-PROTEIN AND RNA-PROTEIN INTERACTIONS IN THE RNA EXOSOME

We recently developed a new zebrafish model of the rare neurodegenerative disease pontocerebellar hypoplasia type 1B (PCH1B).  Our rationally designed small-molecule binds to the cap protein EXOSC3, interfering with RNA binding and recapitulating key features of this disease.  This model system provides a platform to screen for new therapeutic approaches for neurodegenerative diseases.

RNA-PROTEIN INTERACTIONS IN ALS

A hallmark of amyotrophic lateral sclerosis (ALS) is the presence of protein-RNA inclusions containing the RNA-binding protein TDP-43.  We are developing small molecules to treat ALS by targeting TDP-43.  In one approach, we aim to disrupt aberrant polymerization driven by self-association of the N-terminal domain.  In another, we aim to disrupt association of the RRM domains with aberrant RNA.

PROTEIN-PROTEIN INTERACTIONS IN AMP-AD TARGETS

Alzheimer's disease is the most common cause of dementia and has no cure.  The Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) project aims to shorten the time between drug discovery and preclinical validation.  We are focused on targeting the interaction between CD44 and three FERM domain proteins in the target list: EPB41L3, Moesin and FERMT2.

PHARMACOLOGICAL CHAPERONES FOR CLN2

Batten disease comprises a group of rare pediatric neurodegenerative disorders with no cure. A disease modifying treatment (Brineura) for the CLN2 form of Batten requires an invasive procedure and has undesirable side-effects. CLN2 is caused by misfolding of tripeptidyl peptidase 1.  We are targeting tripeptidyl peptidase 1 with pharmacological chaperones to stabilize the folded structure and increase the amount of active enzyme that reaches the lysosome.