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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang Dec 2016

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Thompson Lab Publications

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early ...


Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun Nov 2016

Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun

Pharmacy Faculty Articles and Research

Derivatives of dasatinib were synthesized via esterification with 25 carboxylic acids including amino acids and fatty acids by extending the inhibitor to interact with more diverse sites and to improve specificity. Dasatinib-L-arginine derivative (Das-R, 7) was the most potent of the inhibitors tested with IC50 values of 4.4 nM, <0.25 nM, and <0.45 nM against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src belonged to compound 18 (Das-C10) with an IC50 of 3.2 μM for Csk compared to 35 nM for Src. Furthermore, many compounds displayed increased selectivity toward Src, as compared with Abl. Compounds 15 (Das-E) and 13 (Das-C) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50 ratios). Das-R (IC50 = 2.06 μM) was significantly more potent than Das (IC50 = 26.3 μM) against Panc-1 cells while they both showed an IC50 < 51.2 pM against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed a good agreement with the experimental results and rationalized differences in selectivity of the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of dasatinib scaffold, providing useful insights into mechanisms of kinase selectivity.


Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables May 2016

Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables

Open Access Articles

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum ...


Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson Mar 2016

Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson

Thompson Lab Publications

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone arginine modifications have been linked to the development of several diseases including cancer. In recent years, great progress has been made in understanding the physiological role of individual arginine modifications and their effects on chromatin function. The present review aims to summarize the structural and functional aspects of histone arginine modifying enzymes and their impact on gene transcription. We will discuss the potential for targeting these proteins with small molecules in a variety of disease states.


Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue Feb 2016

Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue

Thompson Lab Publications

Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to ...


Peptidylarginine Deiminase 3 (Pad3) Is Upregulated By Prolactin Stimulation Of Cid-9 Cells And Expressed In The Lactating Mouse Mammary Gland, Guangyuan Li, Isaac N. Hayward, Brittany R. Jenkins, Heather M. Rothfuss, Coleman H. Young, Marja T. Nevalainen, Aaron Muth, Paul R. Thompson, Amy M. Navratil, Brian D. Cherrington Jan 2016

Peptidylarginine Deiminase 3 (Pad3) Is Upregulated By Prolactin Stimulation Of Cid-9 Cells And Expressed In The Lactating Mouse Mammary Gland, Guangyuan Li, Isaac N. Hayward, Brittany R. Jenkins, Heather M. Rothfuss, Coleman H. Young, Marja T. Nevalainen, Aaron Muth, Paul R. Thompson, Amy M. Navratil, Brian D. Cherrington

Thompson Lab Publications

Peptidylarginine deiminases (PADs) post-translationally convert arginine into neutral citrulline residues. Our past work shows that PADs are expressed in the canine and murine mammary glands; however, the mechanisms regulating PAD expression and the function of citrullination in the normal mammary gland are unclear. Therefore, the first objective herein was to investigate regulation of PAD expression in mammary epithelial cells. We first examined PAD levels in CID-9 cells, which were derived from the mammary gland of mid-pregnant mice. PAD3 expression is significantly higher than all other PAD isoforms and mediates protein citrullination in CID-9 cells. We next hypothesized that prolactin regulates ...