THE MAY KHANNA LABORATORY
Developing small molecule therapeutics for neurodegenerative disease
We combine biochemical and biophysical techniques to target key protein-protein and protein-RNA interactions in neurodegenerative disease.
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 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.
MAY KHANNA, PHD
May has over 20 years of experience using multiple biophysical tools including Surface Plasmon Resonance (SPR), Nuclear Magnetic Resonance (NMR) and X-ray Crystallography to define protein-protein, protein-RNA, and and protein-small molecule interactions. Increasing our understanding of these interactions contributes to the development of novel therapeutics for neurodegenerative disease.
LIBERTY FRANÇOIS-MOUTAL, PHD
JONATHAN SANCHEZ, PHD
JUDITH TELLO VEGA, PHD
SAMANTHA PEREZ-MILLER, PHD
AHN LE ANDY
University of Arizona
Department of Pharmacology
Center for Innovation in Brain Science