The Protein Arginine Deiminases: Inhibitors and Characteristics

The Protein Arginine Deiminases: Inhibitors and Characteristics MSc Pharmaceutical Sciences Convocation year of 2015 Elizabeth Joanne Curiel Tejeda Department of Pharmaceutical Sciences University of Toronto Protein arginine deiminases (PADs) are Ca2+ dependent enzymes involved in the post-translational modification of proteins through citrullination. Overexpression of PAD2 and PAD4 has been observed in a number of neurodegenerative diseases. In this thesis, two broad investigations were undertaken to look at the expression patterns of endogenous PADs and how they provide means to the development of disease modifying treatments. First, a BODIPY-based fluorescent probe was designed to assess the expression levels in vitro and in vivo of endogenous PAD. Secondly, medicinal chemistry approaches were adopted to design a library of novel non-covalent compounds to establish a structure activity relationship on PADs and identify a potential hit. Results indicated that a BODIPY-based biomarker was a feasible approach to monitor PAD enzymes in vivo. Through structure-activity relationship investigations, it was established that small heterocycles on an amino acid side chain were contributing to the inhibitory activities towards PADs.M.Sc.2016-12-18 00:00:0