A5068518494- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Thyroid Disorders and Treatments
- Crystallography and molecular interactions
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Peptidase Inhibition and Analysis
- Cell Adhesion Molecules Research
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- Growth Hormone and Insulin-like Growth Factors
- DNA Repair Mechanisms
- Ion channel regulation and function
- Signaling Pathways in Disease
- Chemical Analysis and Environmental Impact
- Monoclonal and Polyclonal Antibodies Research
- Chemical Reaction Mechanisms
- Immune Response and Inflammation
- Inflammasome and immune disorders
- Hormonal Regulation and Hypertension
- Cardiac Fibrosis and Remodeling
- Biochemical effects in animals
- Advanced Wireless Network Optimization
- Click Chemistry and Applications
- Protease and Inhibitor Mechanisms
- Organoselenium and organotellurium chemistry
Indian Institute of Technology Delhi
2023-2024
University of Massachusetts Chan Medical School
2017-2023
Indian Institute of Science Bangalore
2013-2023
University of Michigan
2018
Xiangya Hospital Central South University
2018
Central South University
2018
Chhatrapati Shahu Ji Maharaj University
2011
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, calcium ionophore A23187, nigericin, Candida albicans Group B Streptococcus. studied NET production neutrophils from healthy donors with inhibitors of molecules crucial to PMA-induced NETs including protein kinase C, calcium, reactive oxygen species, enzymes myeloperoxidase (MPO) elastase....
ConspectusProteins are well-known to undergo a variety of post-translational modifications (PTMs). One such PTM is citrullination, an arginine modification that catalyzed by group hydrolases called protein deiminases (PADs). Hundreds proteins known be citrullinated and hypercitrullination associated with autoimmune diseases including rheumatoid arthritis (RA), lupus, ulcerative colitis (UC), Alzheimer's disease, multiple sclerosis (MS), certain cancers. In this Account, we summarize our...
Cd/CB-induced citrullinated vimentin promotes PAD2- and TLR4-dependent lung fibrosis.
Abstract Background Tamoxifen resistance presents a huge clinical challenge for breast cancer patients. An understanding of the mechanisms tamoxifen can guide development efficient therapies to prevent drug resistance. Methods We first tested whether peptidylarginine deiminase 2 (PAD2) may be involved in tamoxifen-resistance cells. The effect depleting or inhibiting PAD2 tamoxifen-resistant MCF-7 (MCF7/TamR) cells was evaluated both vitro and vivo. then investigated potential Cl-amidine, PAD...
Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS generate cGAMP, which binds and STING triggering a conformational change, oligomerization, IRF3- NFκB-dependent transcription type I Interferons (IFNs) cytokines, as well activation autophagy. Aberrant now linked growing number both rare common chronic diseases. Here, we identify characterize potent small-molecule inhibitor STING. This compound,...
The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. may be pathogenic systemic lupus erythematosus (SLE) through its role neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, organ damage. this enzyme mouse models autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO have given conflicting results. SLE has not been...
Abstract Citrullination is a post-translational modification (PTM) of arginine that crucial for several physiological processes, including gene regulation and neutrophil extracellular trap formation. Despite recent advances, studies protein citrullination remain challenging due to the difficulty accessing proteins homogeneously citrullinated at specific site. Herein, we report technology enables site-specific incorporation citrulline (Cit) into in mammalian cells. This approach exploits an...
Given the current impact of SARS-CoV2 and COVID-19 on human health global economy, development direct acting antivirals is paramount importance. Main protease (MPro), a cysteine that cleaves viral polyprotein, essential for replication. Therefore, MPro novel therapeutic target. We identified two inhibitors, D-FFRCMKyne D-FFCitCMKyne, covalently modify active site (C145) determined cocrystal structures. Medicinal chemistry efforts led to SM141 SM142, which adopt unique binding mode within...
Abstract Halogenated nucleosides can be incorporated into the newly synthesized DNA of replicating cells and therefore are commonly used in detection proliferating living tissues. Dehalogenation these modified is one key pathways involved repair mediated by uracil‐DNA glycosylase. Herein, we report first example a selenium‐mediated dehalogenation halogenated nucleosides. We also show that mechanism for debromination remarkably different from deiodination presence ribose or deoxyribose moiety...
Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes that involved in variety human disorders, including cancer and autoimmune diseases. Although targeting PAD4 has shown no benefit sepsis, the role PAD2 remains unknown. Here, we report is engaged sepsis sepsis-induced acute lung injury both patients mice. Pad2–/– or selective inhibition by small molecule inhibitor increased survival improved overall outcomes mouse models sepsis. Pad2 deficiency decreased neutrophil...
Protein arginine deiminase (PAD) enzymes catalyze the conversion of protein-bound into citrulline, an irreversible posttranslational modification with loss a positive charge that can influence protein-protein interactions and protein structure. activity depends on high intracellular calcium concentrations occurring in dying cells. In this study, we demonstrate citrullination is common during pyroptotic cell death macrophages inhibition PAD enzyme by Cl-amidine, pan-PAD inhibitor, blocks...
Protein citrullination plays a role in several autoimmune diseases. Its involvement murine and human type 1 diabetes has recently been recognized through the discovery of antibodies T-cell reactivity against citrullinated peptides. In current study, we demonstrate that systemic inhibition peptidylarginine deiminases (PADs), enzymes mediating citrullination, BB-Cl-amidine treatment, prevents development NOD mice. This prevention was associated with reduced levels pancreas, decreased...
Citrullination, the conversion of peptidyl-arginine into peptidyl-citrulline, is involved in breakage self-tolerance anti-CCP-positive rheumatoid arthritis. This reaction catalyzed by peptidyl arginine deiminases (PADs), which PAD2 and PAD4 are thought to play key pathogenic roles. Small-molecule PAD inhibitors such as pan-PAD inhibitor BB-Cl-amidine, PAD2-specific AFM-30a, PAD4-specific GSK199 hold therapeutic potential useful tools studies citrullination. Using an ELISA based on...
Abstract Thyroid hormones regulate almost every process in the body, including body temperature, growth, and heart rate. They influence carbohydrate metabolism, protein synthesis breakdown, cardiovascular, renal, brain function. Two new polymorphs of synthetic L ‐thyroxine (T4) are reported effect polymorphism on solubility this important hormone is shown. Conformational changes were also discovered to have a remarkable strength halogen bonding reactivity CI bonds, which could significant activity.
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, development PAD inhibitors has drawn significant research interest recent years. Herein, we describe first photoswitchable inhibitors. These compounds possess azobenzene photoswitch to optically control activity. Screening a series structurally similar BB-Cl-amidine afforded 1 2 as most...
Abstract Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation implicated in pathogenesis various types cancers and autoimmune diseases. Consistent with ability human cytomegalovirus (HCMV) to induce post-translational modifications cellular proteins gain a survival advantage, we show that HCMV infection primary fibroblasts triggers PAD-mediated citrullination several host proteins, this activity promotes viral fitness....
The type 1 iodothyronine deiodinase (1D-1) in liver and kidney converts the L-thyroxine (T4), a prohormone, by outer-ring (5') deiodination to biologically active 3,3',5-triiodothyronine (T3) or inner-ring (5) inactive 3,3',5'-triiodothronine (rT3). Sulfate conjugation is an important step irreversible inactivation of thyroid hormones. While sulfate phenolic hydroxyl group stimulates 5-deiodination T4 T3, it blocks 5'-deiodination T4. We show that thyroxine (T4S) undergoes faster as compared...
Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that catalyzed by protein arginine deiminases (PADs), family calcium-regulated enzymes. Aberrantly increased citrullination associated with slew autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) certain cancers. Given clear link between PAD activity human disease, PADs are therapeutically relevant targets. Herein, we report...
Abstract Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation£ of thyroid hormones. It is known iodothyronamines (TnAMs), produced by decarboxylation hormones, act as substrates for deiodinases. To understand whether alters rate and/or regioselectivity deiodination using synthetic deiodinase mimics, we studied different iodothyronamines. The triiodo derivative 3,3′,5‐triiodothyronamine (T3 AM) deiodinated at inner ring...