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.

 
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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.

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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.

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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.

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

We developed a zebrafish model of pontocerebellar hypoplasia type 1B (PCH1B), a rare neurodegenerative disease.  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.

 

RECENT PUBLICATIONS

 
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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

Scientific Reports (2022)

doi/10.1038/s41598-022-12191-8

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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

Frontiers in Molecular Neuroscience (2022)

doi/10.3389/fnmol.2022.883358

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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

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Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape

Liberty Francois-Moutal, David Donald Scott, May Khanna

RSC Chemical Biol​ogy (2021)

10.1039/d1cb00110h

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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

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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)

doi: 10.1021/acschembio.0c00494

PEOPLE

 

Principal Investigator

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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.​

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Post-Doctoral Fellows

JONATHAN SANCHEZ, PHD
JUDITH TELLO VEGA, PHD

Graduate Students

LIPSA JENA

DAVID D. SCOTT

Undergraduate Researchers

Lab Technicians

JAKE CARLSON

Research Scientist

SAMANTHA PEREZ-MILLER, PHD

Alumni

RAZAZ FELEMBAM, PHD

VICTOR G. MIRANDA, BS

NILOUFAR MOLLASALEHI, PHD

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CONTACT US

Department of Molecular Pathobiology
NYU College of Dentistry
345 E. 24th Street

New York, NY 10010

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