Protein Arginine Deiminase 4 (PAD4) is widely regarded in the Rheumatoid Arthritis (RA) community as the best new target for the development of a novel RA therapeutic. This enzyme hydrolyses Arg residues to form Citrulline and ammonia. The first goal of this proposal is to perform structure/activity relationships on F-Amidine, a fluoroacetamidine-based PAD4 inactivator discovered by the PI; and thereby identify a PAD4 inactivator with improved potency. The second goal is to take two approaches to identify a PAD4-selective inactivator. The first approach incorporates the haloacetamidine warhead into PAD-specific peptide substr- ates - substrate specificity studies will be used to identify these peptides. The second approach uses a focused library of haloacetamidine-containing compounds - inactivators with improved selectivity willbe identified by screening the library with PAD4 and PAD2, a related enzyme that is the most widely expressed PAD isozyme. The third goal of this proposal is the use these haloacetamidine based compounds as the basis for synthesizing Activity Based Protein Profiling (ABPPs) Reagents. These ABPPs will not only be useful for characterizing the in vivo selectivity of PAD4 inactivators, but will also enable the isolation and/or enrichment of endogenous PAD4 from mammalian cell lines; and thereby facilitate the identification of the post-translational modifications that occur to this protein when it is activated in vivo. Once complete the proposed studies will lead to the identification of a potent and selective PAD4 inacti- vator that will represent a lead compound for the treatment of RA. In addition, the proposed compounds will be important probes that will be used to decipher the incompletely defined role of PAD4 in human cell signaling (e.g. gene regulation) and how (or if) dysregulation of these pathways contributes to RA. Lay Statement: The goal of this project is to develop inhibitors targeting Protein Arginine Deiminase 4. This goal is being pursued because the activity of this enzyme, when dysregulated, is believed to contribute to the onset and progression of RA, a disease that affects ~1% of the American population and causes a mean reduction in life expectancy of 5 to 10 years. The inhibitors described in this proposal not only represent lead compounds for the treatment of RA but will also be useful for further defining how this enzyme contributes to disease onset.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Carolina at Columbia
Schools of Arts and Sciences
United States
Zip Code
Mohamed, Bashir M; Boyle, Noreen T; Schinwald, Anja et al. (2018) Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials. Sci Rep 8:679
Young, Coleman H; Rothfuss, Heather M; Gard, Philip F et al. (2017) Citrullination regulates the expression of insulin-like growth factor-binding protein 1 (IGFBP1) in ovine uterine luminal epithelial cells. Reproduction 153:1-10
Kosgodage, Uchini S; Trindade, Rita P; Thompson, Paul R et al. (2017) Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition of Exosome and Microvesicle Release and Enhanced Efficacy of Cancer Chemotherapy. Int J Mol Sci 18:
Clancy, Kathleen W; Russell, Anna-Maria; Subramanian, Venkataraman et al. (2017) Citrullination/Methylation Crosstalk on Histone H3 Regulates ER-Target Gene Transcription. ACS Chem Biol 12:1691-1702
Carmona-Rivera, Carmelo; Carlucci, Philip M; Moore, Erica et al. (2017) Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol 2:
Muth, Aaron; Subramanian, Venkataraman; Beaumont, Edward et al. (2017) Development of a Selective Inhibitor of Protein Arginine Deiminase 2. J Med Chem 60:3198-3211
Sun, Bo; Dwivedi, Nishant; Bechtel, Tyler J et al. (2017) Citrullination of NF-?B p65 promotes its nuclear localization and TLR-induced expression of IL-1? and TNF?. Sci Immunol 2:
Clancy, Kathleen W; Weerapana, Eranthie; Thompson, Paul R (2016) Detection and identification of protein citrullination in complex biological systems. Curr Opin Chem Biol 30:1-6
Kawalkowska, Joanna; Quirke, Anne-Marie; Ghari, Fatemeh et al. (2016) Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses. Sci Rep 6:26430
Li, Guangyuan; Hayward, Isaac N; Jenkins, Brittany R et al. (2016) Peptidylarginine Deiminase 3 (PAD3) Is Upregulated by Prolactin Stimulation of CID-9 Cells and Expressed in the Lactating Mouse Mammary Gland. PLoS One 11:e0147503

Showing the most recent 10 out of 78 publications