Our Collaborators
ENZYME INHIBITION AND DEVELOPMENT OF SMALL MOLECULE INHIBITORS OF GABA TRANSAMINASE FOR DIABETES TREATMENT
The severity and incidence of type 2 diabetes is directly related to fat accumulation in the liver. We have shown that liver fat accumulation increases liver production and release of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. Liver produced GABA stimulates insulin release and causes insulin resistance at skeletal muscle. This GABA is produced by GABA transaminase and production can be eliminated by inhibiting GABA transaminase. Inhibiting GABA transaminase rapidly restores insulin sensitivity and normo-insulinemia in diet-induced obese mice.
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RNA-PROTEIN INTERACTIONS IN ALS
Transactive response DNA Biding Protein (TDP-43) is involved in multiple steps of RNA processing that has been shown to be mislocalize in the cytoplasm in diseases such as ALS and Alzheimer's Disease. In collaboration with Dr. Alison Axtman, we are developing new generation of compounds that specifically target TDP-43 in pathological conditions.
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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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