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Our Collaborators

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

The RNA exosome processes coding and noncoding RNA substrates in the nucleus and cytoplasm of all eukaryotic cells.  Our collaborator Joanna Jen (Mt Sanai Hospital), identified multiple recessive mutations in subunit 3 (EXOSC3) linked to infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly, and pontocerebellar hypoplasia type 1 (PCH1B).  We are examining how these mutations affect interactions between the exosome and RNA substrates.

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RNA-PROTEIN INTERACTIONS IN ALS

Transactive response DNA Biding Protein (TDP-43) is involved in multiple steps of RNA processing.  Insoluble inclusions marked by TDP-43 are found in 95% of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobe Degeneration (FTLD) patients.  These are progressive neurodegenerative diseases with no cure.  In collaboration with Professor Daniela Zarnescu (Molecular and Cellular Biology Department, University of Arizona) we are examining the link between TDP-43 and ALS-FTLD.

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PROTEIN-PROTEIN INTERACTIONS IN THE NECROSOME

Necroptosis is misregulated in several neurodegenerative diseases, contributing to neuronal cell death and neuroinflammation 

With Salvator Oddo (Neurodegenerative Disease Research Center, Arizona State University), we are developing compounds to disrupt the interactions between key proteins in this pathway.

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PROTEIN-PROTEIN INTERACTIONS IN AMP-AD TARGETS

CD44 is an extracellular adhesion molecule involved in neuroinflammation associated with Alzheimer's disease.  Signal transduction through CD44 requires binding to a cytoplasmic FERM domain protein.  In collaboration with Opher Gileadi (Nuffield Department of Medicine, University of Oxford) and Lara Mangravite (Sage Bionetworks), we are working to develop small molecule inhibitors of this interaction.

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Pharmacological Chaperones for CLN2

Tripeptidyl peptidase 1 (CLN2) is a lysosomal enzyme that is expressed as a proenzyme. In collaboration with Jill Weimer (Sanford Research), we are targeting several potential sites with the goal of stabilizing the native fold of the CLN2 proenzyme. The idea is that a small molecule chaperone will increase the amount of correctly folded CLN2 proenzyme which will permit recognition by glycosylation machinery within the endoplasmic reticulum, permitting trafficking through the endosomal-lysosomal pathway and increasing the amount of CLN2 proenzyme that reaches the lysosome.  We are targeting several sites distal to the active site and propeptide interface in order to avoid interference with activation and ideally, continue to stabilize the active form after propeptide cleavage in the lysosome.

DRUG DISCOVERY AND DEVELOPMENT

One of our primary goals is to develop lead compounds that modulate protein-protein or protein-RNA interactions.  Large scale virtual screening, docking, and SAR development is done in collaboration with Marcel Patek, founder and president of Bright Rock Path, LLC and with  Vijay Gokhale at the University of Arizona BIO5 Institute.

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