We combine biochemical and biophysical techniques to target key protein-protein and protein-RNA interactions in neurodegenerative disease.
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 The Necrosome
Chronic inflammation initiates necroptosis, a poorly understood pathway of programmed cell death. This pathway is mediated by RIPK1 phosphorylation of RIPK3 followed by RIPK3 phosphorylation of MLKL. We are developing compounds to disrupt the interactions between these proteins without interfering with their normal, vital cell functions.
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.
Enzyme Inhibition and Development of Small Molecule Inhibitors of Gaba Transaminase for Diabetes Treatment
In collaboration with the Renquist laboratory at the University of Arizona, we are developing inhibitors of GABA transaminase to develop therapeutics for Diabetes. Our goal is to develop and validate novel, specific, highly effective, blood brain barrier impenetrable GABA-transaminase inhibitors.
Targeting RNA With Small Molecules
Our research aims to develop small-molecule therapies that modulate RNA splicing or stability to restore gene expression disrupted by frameshifting or nonsense mutations. This “gene salvaging” approach seeks to rescue protein function in variants inactivated by premature stop codons, such as those leading to mRNA degradation and production of truncated protein. By progressing from in silico design through structural biology, biophysics, and cell-based assays, we can discover and optimize new compounds that effectively target RNA. While splice-switching ASOs can promote exon skipping to restore partially functional protein when combined with existing modulators, they face delivery limitations and still require small-molecule potentiators or activators. We are pursuing small molecules used alone or in combination with ASOs that offer improved bioavailability, simplified administration, and enhanced therapeutic potential for patients with such genetic variants.
