THE MAY KHANNA LABORATORY
Developing small molecule therapeutics for neurodegenerative disease
RESEARCH HIGHLIGHTS
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.
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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.
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.
RECENT PUBLICATIONS
Identifying interactions between TDP-43’s N-terminal and
RNA-binding domains
David D. Scott, Lipsa Jenna, Akash Rajaram, Jason Ang, Samantha Perez-Miller, Vlad Kumirov, Rajesh Khanna & May Khanna
Heat shock protein Grp78/BiP/HspA5 binds directly to TDP-43 and mitigates toxicity associated with disease pathology
Liberty François-Moutal, David Donald Scott, Andrew J. Ambrose, Christopher J. Zerio, Marina Rodriguez-Sanchez, Kumara Dissanayake, Danielle G. May, Jacob M. Carlson, Edward Barbieri, Aubin Moutal, Kyle J. Roux, James Shorter, Rajesh Khanna, Sami J. Barmada, Leeanne McGurk & May Khanna
Animal Models of Neurodegenerative Disease: Recent Advances in Fly Highlight Innovative Approaches to Drug Discovery
Judith A Tello, Haley E Williams, Robert M Eppler, Michelle L Steinhilb, and May Khanna
Aptamers Targeting Hallmark Proteins of Neurodegeneration
Niloufar Mollasalehi, Liberty Francois-Moutal, David Porciani, Donald H. Burke, and May Khanna
Nucleic Acid Therapeutics (2022)
doi/10.1089/nat.2021.0091
Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape
Liberty Francois-Moutal, David Donald Scott, May Khanna
RSC Chemical Biology (2021)
10.1039/d1cb00110h
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)
10.1021/acsmedchemlett.1c00060
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)
PEOPLE
Principal Investigator
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.
Post-Doctoral Fellows
Graduate Students
Tolga Catmakas, Ph.D.
Lab Technicians
Lipsa Jena
Akash Rajaram
Hunter Reyes, M.Sc.
Research Scientist
Samantha Perez-Miller, Ph.D.
Judith Tello Vega, Ph.D.
Marina Sanchez Rodriguez, Ph.D
Niloofar Ghadirian, Ph.D.
Alumni
Razaz Felemban, Ph.D. (Assistant Professor; Saudi Arabia)
Niloufar Mollasalehi, Ph.D. (Scientist Beckman Coulter)
David D. Scott, Ph.D (Senior Scientist at Manus)
Liberty Francois-Moutal, Ph.D (Assistant Professor, SLU)
Jonathan Sanchez, Ph.D. (Co-founder and CSO Regenerix; Scientist at Roche)
Éverton Dias D’Andréa (Postdoc, Austria)
Victor G. Miranda, B.S. (Ph.D. in Chemical biology, Harvard)
Haley E. Williams, M.S. (UNC, clinical dietician)
Franky Torres, BS (Medical school, 2024)
CONTACT US
University of Florida College of Medicine
Department of Pharmacology & Therapeutics
Gainesville, FL 32610