Graduate Program

Chemistry

Degree Name

Master of Science (MS)

Semester of Degree Completion

Summer 2020

Thesis Director

Michael W. Beck

Thesis Committee Member

Gopal R. Periyannan

Thesis Committee Member

Hongshan He

Thesis Committee Member

Zhiqing Yan

Abstract

Peroxisomes are dynamic and interconnected single lipid membrane bound organelles found in the eukaryotic cells which are involved in various biochemical processes including the b-oxidation of very long chain and branched chain fatty acids, metabolism of reactive oxygen and nitrogen species, and reduction of hydrogen peroxide among others. These organelles are known to host numerous proteins and enzymes depending on the cellular environment. All of the proteins needed in the peroxisomes are encoded in the nucleus and synthesized in the cytosol which are then transported to the peroxisomes with the help of a sophisticated protein-transport machinery. Pex5 is one of the key transport proteins responsible for carrying proteins tagged with the peroxisome targeting sequence 1 (PTS-1). Despite peroxisomes being continuously investigated by the scientific community since their discovery in 1954, there is no reported small molecule that can inhibit Pex5 to modulate peroxisome protein import in humans to date. To address this, a small molecule chemical tool, PROTAC1, was designed based on the PROteolysis TArgeting Chimera (PROTAC) technology. PROTAC1 and CPP1, a fluorophore designed to help evaluate the efficiency of peroxisome import, were synthesized and characterized by NMR, HPLC, and ESI-MS. Subsequent preliminary Western blotting studies indicate that PROTAC1 can degrade Pex5 in HEK293T cells. This suggests that the PROTAC technology may be a viable approach to develop inhibitors of Pex5-mediated peroxisomal protein import in human cells.

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