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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed Mar 2019

Purification And Characterization Of A Nonspecific Lipid Transfer Protein 1 (Nsltp1) From Ajwain (Trachyspermum Ammi) Seeds, Meshal Nazeer, Humera Waheed, Maria Saeed, Saman Yousuf Ali, M. Iqbal Choudhary, Zaheer Ul-Haq, Aftab Ahmed

Pharmacy Faculty Articles and Research

Ajwain (Trachyspermum ammi) belongs to the family Umbelliferae, is commonly used in traditional, and folk medicine due to its carminative, stimulant, antiseptic, diuretic, antihypertensive, and hepatoprotective activities. Non-specific lipid transfer proteins (nsLTPs) reported from various plants are known to be involved in transferring lipids between membranes and in plants defense response. Here, we describe the complete primary structure of a monomeric non-specific lipid transfer protein 1 (nsLTP1), with molecular weight of 9.66 kDa, from ajwain seeds. The nsLTP1 has been purified by combination of chromatographic techniques, and further characterized by mass spectrometry, and Edman degradation. The ajwain nsLTP1 is ...


Thioredoxin Modulates Protein Arginine Deiminase 4 (Pad4)-Catalyzed Citrullination, Mitesh Nagar, Ronak Tilvawala, Paul R. Thompson Feb 2019

Thioredoxin Modulates Protein Arginine Deiminase 4 (Pad4)-Catalyzed Citrullination, Mitesh Nagar, Ronak Tilvawala, Paul R. Thompson

Open Access Articles

Protein citrullination is a post-translational modification catalyzed by the protein arginine deiminases (PADs). This modification plays a crucial role in the pathophysiology of numerous autoimmune disorders including RA. Recently, there has been a growing interest in investigating physiological regulators of PAD activity to understand the primary cause of the associated disorders. Apart from calcium, it is well-documented that a reducing environment activates the PADs. Although the concentration of thioredoxin (hTRX), an oxidoreductase that maintains the cellular reducing environment, is elevated in RA patients, its contribution toward RA progression or PAD activity has not been explored. Herein, we demonstrate that hTRX ...


Peptidylarginine Deiminases 2 And 4 Modulate Innate And Adaptive Immune Responses In Tlr-7-Dependent Lupus., Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson Dec 2018

Peptidylarginine Deiminases 2 And 4 Modulate Innate And Adaptive Immune Responses In Tlr-7-Dependent Lupus., Yudong Liu, Yaíma L Lightfoot, Nickie Seto, Santanu Mondal, Padmavathy Nandha Premnath, Paul R. Thompson

University of Massachusetts Medical School Publications

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO models have given conflicting results. The role of PAD2 in SLE has not been investigated. The differential roles of PAD2 and PAD4 in TLR-7-dependent lupus autoimmunity were examined. Padi4-/- displayed decreased autoantibodies, type I IFN responses, immune ...


Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington Sep 2018

Histone Citrullination Represses Mirna Expression Resulting In Increased Oncogene Mrnas In Somatolactotrope Cells., Stanley B Devore, Coleman H. Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R. Thompson, Brian D. Cherrington

University of Massachusetts Medical School Publications

Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA-sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR-23b and miR-29c is suppressed by histone ...


T Cell Epitope Engineering: An Avian H7n9 Influenza Vaccine Strategy For Pandemic Preparedness And Response, Leonard Moise, Bethany M. Biron, Christine M. Boyle, Nese Kurt Yilmaz, Hyesun Jang, Celia A. Schiffer, Ted M. Ross, William D. Martin, Anne S. De Groot Sep 2018

T Cell Epitope Engineering: An Avian H7n9 Influenza Vaccine Strategy For Pandemic Preparedness And Response, Leonard Moise, Bethany M. Biron, Christine M. Boyle, Nese Kurt Yilmaz, Hyesun Jang, Celia A. Schiffer, Ted M. Ross, William D. Martin, Anne S. De Groot

Schiffer Lab Publications

The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, speed and capacity have been achieved but vaccine effectiveness remains a significant challenge. Here, we describe a novel vaccine design strategy called immune engineering in the context of H7N9 influenza vaccine development. The approach combines immunoinformatic and structure modeling methods to promote protective antibody responses against H7N9 hemagglutinin (HA) by engineering whole antigens to carry seasonal influenza HA memory CD4(+) T cell epitopes - without perturbing native antigen structure - by galvanizing HA-specific memory ...


Assembly Of Human C-Terminal Binding Protein (Ctbp) Into Tetramers, Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer Jun 2018

Assembly Of Human C-Terminal Binding Protein (Ctbp) Into Tetramers, Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer

Schiffer Lab Publications

C-terminal binding protein 1 (CtBP1) and CtBP2 are transcriptional coregulators that repress numerous cellular processes, such as apoptosis, by binding transcription factors and recruiting chromatin-remodeling enzymes to gene promoters. The NAD(H)-linked oligomerization of human CtBP is coupled to its co-transcriptional activity, which is implicated in cancer progression. However, the biologically relevant level of CtBP assembly has not been firmly established; nor has the stereochemical arrangement of the subunits above that of a dimer. Here, multi-angle light scattering (MALS) data established the NAD(+)- and NADH-dependent assembly of CtBP1 and CtBP2 into tetramers. An examination of subunit interactions within CtBP1 ...


Photochemical Control Of Protein Arginine Deiminase (Pad) Activity, Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson Apr 2018

Photochemical Control Of Protein Arginine Deiminase (Pad) Activity, Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson

Thompson Lab Publications

Protein Arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis and breast cancer. Therefore, the development of PAD-inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD-inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-Amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis-isomer of 1 is 10-fold more potent than its trans-isomer, whereas the trans-isomer of ...


Donated Chemical Probes For Open Science, Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow Apr 2018

Donated Chemical Probes For Open Science, Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow

Open Access Articles

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of ...


The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson Mar 2018

The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson

Thompson Lab Publications

Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and "clickable" probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced ...


In Vitro Label Free Screening Of Chemotherapeutic Drugs Using Raman Micro-Spectroscopy: Towards A New Paradigm Of Spectralomics., Zeineb Farhane, Haq Nawaz, Franck Bonnier, Hugh Byrne Mar 2018

In Vitro Label Free Screening Of Chemotherapeutic Drugs Using Raman Micro-Spectroscopy: Towards A New Paradigm Of Spectralomics., Zeineb Farhane, Haq Nawaz, Franck Bonnier, Hugh Byrne

Articles

This overview groups some of the recent studies highlighting the potential application of Raman micro-spectroscopy as an analytical technique in preclinical development to predict drug mechanism of action and in clinical application as a companion diagnostic and in personalised therapy due to its capacity to predict cellular resistance and therefore to optimise chemotherapeutic treatment efficacy.

Notably, the anthracyclines, Doxorubicin and Actinomycin D, elicit similar spectroscopic signatures of subcellular interaction characteristic of the mode of action of intercalation. Although Cisplatin and Vincristine show markedly different signatures, at low exposure doses, their signatures at higher doses show marked similarities to those elicited ...


Comparison Of Partially And Fully Chemically-Modified Sirna In Conjugate-Mediated Delivery In Vivo, Matthew R. Hassler, Anton A. Turanov, Julia F. Alterman, Reka A. Haraszti, Andrew H. Coles, Maire F. Osborn, Dimas Echeverria, Mehran Nikan, William E. Salomon, Loic Roux, Bruno M. D. C. Godinho, Sarah M. Davis, David V. Morrissey, Phillip D. Zamore, S. Ananth Karumanchi, Melissa J. Moore, Neil Aronin, Anastasia Khvorova Feb 2018

Comparison Of Partially And Fully Chemically-Modified Sirna In Conjugate-Mediated Delivery In Vivo, Matthew R. Hassler, Anton A. Turanov, Julia F. Alterman, Reka A. Haraszti, Andrew H. Coles, Maire F. Osborn, Dimas Echeverria, Mehran Nikan, William E. Salomon, Loic Roux, Bruno M. D. C. Godinho, Sarah M. Davis, David V. Morrissey, Phillip D. Zamore, S. Ananth Karumanchi, Melissa J. Moore, Neil Aronin, Anastasia Khvorova

Open Access Articles

Small interfering RNA (siRNA)-based drugs require chemical modifications or formulation to promote stability, minimize innate immunity, and enable delivery to target tissues. Partially modified siRNAs (up to 70% of the nucleotides) provide significant stabilization in vitro and are commercially available; thus are commonly used to evaluate efficacy of bio-conjugates for in vivo delivery. In contrast, most clinically-advanced non-formulated compounds, using conjugation as a delivery strategy, are fully chemically modified (100% of nucleotides). Here, we compare partially and fully chemically modified siRNAs in conjugate mediated delivery. We show that fully modified siRNAs are retained at 100x greater levels in various ...


Structural Determination Of The Broadly Reactive Anti-Ighv1-69 Anti-Idiotypic Antibody G6 And Its Idiotope, Yuval Avnir, Kristina L. Prachanronarong, Shurong Hou, Brendan J. Hilbert, Markus-Frederik Bohn, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang, Nese Kurt Yilmaz, Celia A. Schiffer, Wayne A. Marasco Dec 2017

Structural Determination Of The Broadly Reactive Anti-Ighv1-69 Anti-Idiotypic Antibody G6 And Its Idiotope, Yuval Avnir, Kristina L. Prachanronarong, Shurong Hou, Brendan J. Hilbert, Markus-Frederik Bohn, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang, Nese Kurt Yilmaz, Celia A. Schiffer, Wayne A. Marasco

Schiffer Lab Publications

The heavy chain IGHV1-69 germline gene exhibits a high level of polymorphism and shows biased use in protective antibody (Ab) responses to infections and vaccines. It is also highly expressed in several B cell malignancies and autoimmune diseases. G6 is an anti-idiotypic monoclonal Ab that selectively binds to IGHV1-69 heavy chain germline gene 51p1 alleles that have been implicated in these Ab responses and disease processes. Here, we determine the co-crystal structure of humanized G6 (hG6.3) in complex with anti-influenza hemagglutinin stem-directed broadly neutralizing Ab D80. The core of the hG6.3 idiotope is a continuous string of CDR-H2 ...


Selective Targeting Of Bromodomains Of The Bromodomain-Phd Fingers Family Impairs Osteoclast Differentiation, Julia C. Meier, Hanna Witwicka, Sung-Yong Hwang, Mark J. Birnbaum, Stefan Knapp Oct 2017

Selective Targeting Of Bromodomains Of The Bromodomain-Phd Fingers Family Impairs Osteoclast Differentiation, Julia C. Meier, Hanna Witwicka, Sung-Yong Hwang, Mark J. Birnbaum, Stefan Knapp

Open Access Articles

Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional ...


Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury Jul 2017

Cellular And Molecular Targets Of Menthol Actions, Murat Oz, Eslam El Nebrisi, Keun-Hang Susan Yang, Frank Christopher Howarth, Lina T. Al Kury

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions ofmenthol. There has been new evidence demonstrating thatmenthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at ...


Inhibiting Translesion Dna Synthesis As An Approach To Combat Drug Resistance To Dna Damaging Agents, Jung-Suk Choi, Seol Kim, Edward Motea, Anthony J. Berdis Jun 2017

Inhibiting Translesion Dna Synthesis As An Approach To Combat Drug Resistance To Dna Damaging Agents, Jung-Suk Choi, Seol Kim, Edward Motea, Anthony J. Berdis

Chemistry Faculty Publications

Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced ...


Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky Jun 2017

Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky

Thompson Lab Publications

Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a ...


Role Of Peptidylarginine Deiminase 2 (Pad2) In Mammary Carcinoma Cell Migration, Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. Mcelwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod May 2017

Role Of Peptidylarginine Deiminase 2 (Pad2) In Mammary Carcinoma Cell Migration, Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. Mcelwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.

METHODS: For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer May 2017

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer Apr 2017

Dengue Virus Ns2b/Ns3 Protease Inhibitors Exploiting The Prime Side, Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I. Soumana, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and subtropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing of 8 of the 13 substrate cleavage sites by dengue virus NS2B/NS3 protease. With no available direct-acting antiviral targeting DENV, NS2/NS3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds. However, the prime side also significantly modulates DENV protease binding affinity, as revealed by engineering the binding loop of aprotinin, a ...


Ligands Of Therapeutic Utility For The Liver X Receptors., Rajesh Komati, Dominick Spadoni, Shilong Zheng, Jayalakshmi Sridhar Jan 2017

Ligands Of Therapeutic Utility For The Liver X Receptors., Rajesh Komati, Dominick Spadoni, Shilong Zheng, Jayalakshmi Sridhar

Faculty and Staff Publications

Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism ...


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 ...


Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham Jun 2016

Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham

FIU Electronic Theses and Dissertations

Downstream regulatory element antagonist modulator (DREAM) is involved in various interactions with targets both inside and outside of the nucleus. In the cytoplasm, DREAM interacts with the C-terminal fragments of presenilins to facilitate the production of β-amyloid plaques in Alzheimer’s disease. In the nucleus, Ca2+ free DREAM directly binds to specific downstream regulatory elements of prodynorphin/c-fos gene to repress the gene transcription in pain modulation. These interactions are regulated by Ca2+ and/or Mg2+ association at the EF-hands in DREAM. Therefore, understanding the conformational dynamics and stability associated with Ca2+ and/or Mg ...


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 ...


Molecular Targeting Of Protein Arginine Deiminases To Suppress Colitis And Prevent Colon Cancer, Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth Nov 2015

Molecular Targeting Of Protein Arginine Deiminases To Suppress Colitis And Prevent Colon Cancer, Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth

Thompson Lab Publications

Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and rectal bleeding. The extent of these symptoms depends on disease severity. The protein arginine deiminase (PAD) family of enzymes converts peptidyl-Arginine to peptidyl-Citrulline through citrullination. PADs are dysregulated, with abnormal citrullination in many diseases, including UC and colorectal cancer (CRC). We have developed the small molecule, pan-PAD inhibitor, Chlor-amidine (Cl-amidine), with multiple goals, including treating UC and preventing CRC. Building off our recent results showing that: 1) Cl-amidine suppresses colitis in vivo in a dextran ...


Anti-Tb And Antibacterial Activities Of Natural Products Extracts, Douglas Armstrong, Nathan Krause, Drew Frey Oct 2015

Anti-Tb And Antibacterial Activities Of Natural Products Extracts, Douglas Armstrong, Nathan Krause, Drew Frey

Faculty Scholarship – Chemistry

Samples of numerous plant species were received from the southwestern part of the USA from Richard Spjut, and plant samples were collected here in Illinois. All were extracted with typical solvents, giving crude residues, some of which were subjected to counter-current or flash chromatographic methods. Some of the crude extracts and chromatographic fractions had anti-tuberculosis and/or antibacterial activity.

In a general way, bioactive natural products are dealt with very well by Liang & Fang, 2006. More specifically, the southwestern part of the United States has a large variety of indigenous plants, many of which have not been investigated for their ...


Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania V. Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill A. Zitzewitz, John E. Landers, Bruce L. Goode, Celia A. Schiffer, Daryl A. Bosco Jun 2015

Structural Basis For Mutation-Induced Destabilization Of Profilin 1 In Als, Sivakumar Boopathy, Tania V. Silvas, Maeve Tischbein, Silvia Jansen, Shivender Shandilya, Jill A. Zitzewitz, John E. Landers, Bruce L. Goode, Celia A. Schiffer, Daryl A. Bosco

Schiffer Lab Publications

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the ...


Chemical Biology Of Protein Arginine Modifications In Epigenetic Regulation, Jakob Fuhrmann, Kathleen W. Clancy, Paul R. Thompson Jun 2015

Chemical Biology Of Protein Arginine Modifications In Epigenetic Regulation, Jakob Fuhrmann, Kathleen W. Clancy, Paul R. Thompson

Thompson Lab Publications

Review article on histone citrullination (arginine deimination), histone arginine methylation, and noncanonical histone arginine modifications.