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.
In Silico Targeting of the Long Noncoding RNA MALAT1
Liberty Francois-Moutal, Victor G. Miranda, Niloufar Mollasalehi, Vijay Gokhale, May Khanna
ACS Medicinal Chemistry Letters (2021)
An allosteric modulator of RNA binding targeting the N-terminal domain of TDP-43 yields neuroprotective properties
Niloufar Mollasalehi, Liberty Francois-Moutal, David D. Scott, Judith Arane Tello, Haley Williams, Brendan Mahoney, Jacob M. Carlson, Yue Dong, Xingli Li, Victor G. Miranda, Vijay Gokhale, Wei Wang, Sami J. Barmada, May Khanna
ACS Chemical Biology (2020)
Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-Apoptotic Mcl-1 and Bfl-1 Proteins
Karson J Kump,Lei Miao, Ahmed SA Mady, Nurul H Ansari, Uttar K Shrestha, Yuting Yang, Mohan Pal, Chenzhong Liao, Andrej Perdih, Fardokht A Abulwerdi, Krishnapriya Chinnaswamy, Jennifer L Meagher, Jacob M Carlson, May Khanna, Jeanne A Stuckey, Zaneta Nikolovska-Coleska
Journal of Medicinal Chemistry (2020)
Structural Insights Into TDP-43 and Effects of Post-translational Modifications
Liberty François-Moutal, Samantha Perez-Miller, David D. Scott, Victor Miranda, Niloufar Mollasalehi, and May Khanna
Front. Mol. Neurosci. (2019)
A small molecule targeting TDP-43’s RNA recognition motifs reduces locomotor defects in a Drosophila model of ALS
Liberty François-Moutal, David D. Scott, Razaz Felemban, Victor Miranda, Melissa Sayegh, Samantha Perez-Miller, Rajesh Khanna, Vijay Gokhale, Daniela C. Zarnescu and May Khanna
ACS Chem Biol. (2019) 14(9):2006-2013.
1H, 15N and 13C backbone assignment of apo TDP-43 RNA recognition motifs
David D. Scott, Liberty François-Moutal, Vlad K. Kumirov and May Khanna
Biomolecular NMR Assignments. (2019) 13(1):163-167.
A Chemical Biology Approach to Model Pontocerebellar Hypoplasia Type 1B (PCH1B). ACS Chemical Biology
François-Moutal L, Jahanbakhsh S, Nelson A, Ray D, Scott DD, Hennefarth MR, Moutal A, Perez-Miller S, Al-Shamari A, Coursodon P, Meechoovet B, Reiman R, Lyons E, Beilstein M, Morris QD, Van Keuren-Jensen K, Hughes TR, Khanna R, Koehler C, Jen Joanna, Gokhale V, Khanna M.
ACS Chem Biol. (2018) 13(10):3000-3010.
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 protein-small molecule interactions. Increasing our understanding of these interactions contributes to the development of novel therapeutics for neurodegenerative disease.
EVERTON DIAS D'ANDREA, PHD
LIBERTY FRANÇOIS-MOUTAL, PHD
JONATHAN SANCHEZ, PHD
JUDITH TELLO VEGA, PHD
HALEY E. WILLIAMS
DAVID D. SCOTT
JOHN R. BROWN
MATHEO I. HERRERA
SAMANTHA PEREZ-MILLER, PHD
RAZAZ FELEMBAM, PHD
VICTOR G. MIRANDA, BS
NILOUFAR MOLLASALEHI, PHD
University of Arizona
Department of Pharmacology
Center for Innovation in Brain Science