Development of Sulfonyl-triazole Exchange (SuTEx) Molecules for Live-cell Protein Profiling via Quantitative Proteomics Methods 399 views

With the rapid development of chemical proteomics, our understanding of previously unreachable biological space are now possible. Chemical proteomics (chemoproteomics) provides unique opportunities for ligand discovery in a functionally-dependent setting. Activity-based protein profiling (ABPP) is a prominent example of chemoproteomics that uses activity-based probes to determine amino acid reactivity and functionality of proteins in a native biological setting. The “druggability” profiles within the proteome could be a snapshot of the availability of protein sites that are dependent on the cellular regulation of protein functions. Developing new chemical probes that target protein sites beyond active sites could reveal new druggable pockets and the investigation of these sites could provide us insights into protein functions, such as allosteric regulation, autoinhibitory mechanism and RNA/DNA binding/regulation. This dissertation presents work on a more recently discovered family of chemical probes using sulfur-triazole exchange (SuTEx) chemistry and focuses on expanding the SuTEx chemistry toolbox. It also presents work on validating the SuTEx chemistry toolbox for chemoproteomic applications and the development of a relatively quantitative proteomics workflow to aid the SuTEx ligand discovery effort.

PHD (Doctor of Philosophy)

Chemoproteomcis; quantitative proteomics; tandem mass spectrometry; sulfur-triazole exchange chemistry (SuTEx); Activity based protein profiling (ABPP); covalent kinase probe; covalent ligand discovery

English

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2022-12-02