Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors

Mondal, Santanu; Gong, Xuefeng; Zhang, Xiaoqian; Salinger, Ari J.; Zheng, Li; Sen, Sudeshna; Weerapana, Eranthie; Zhang, Xuesen; Thompson, Paul R.

doi:10.1002/ange.201906334

Cited by 4 publications

(3 citation statements)

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“…We also reported selective inhibitors for PADs 1 and 2. These compounds include SM26 (figure 2a) which selectively inhibits PAD1 [55]. Notably, the potency and selectivity of this compound is owing in part to the formation of halogen bonds between the enzyme and PAD1 [55].…”

Section: Selective Protein Arginine Deiminase Inhibitorsmentioning

confidence: 99%

“…These compounds include SM26 (figure 2a) which selectively inhibits PAD1 [55]. Notably, the potency and selectivity of this compound is owing in part to the formation of halogen bonds between the enzyme and PAD1 [55]. SM26 is highly potent in cells and inhibits histone H3 citrullination in HEK293T cells engineered to overexpress PAD1 as well as in mouse embryos where PAD1 inhibition blocks embryonic development at the morula stage.…”

Section: Selective Protein Arginine Deiminase Inhibitorsmentioning

confidence: 99%

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Protein citrullination: inhibition, identification and insertion

Barasa,

Thompson

2023

Phil. Trans. R. Soc. B

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Protein citrullination is a post-translational modification (PTM) that is catalysed by the protein arginine deiminase (PAD) family of enzymes. This PTM involves the transformation of an arginine residue into citrulline. Protein citrullination is associated with several physiological processes, including the epigenetic regulation of gene expression, neutrophil extracellular trap formation and DNA damage-induced apoptosis. Aberrant protein citrullination is relevant to several autoimmune and neurodegenerative diseases and certain forms of cancer. PAD inhibitors have shown remarkable efficacy in a range of diseases including rheumatoid arthritis (RA), lupus, atherosclerosis and ulcerative colitis. In RA, anti-citrullinated protein antibodies can be detected prior to disease onset and are thus a valuable diagnostic tool for RA. Notably, citrullinated proteins may serve more generally as biomarkers of specific disease states; however, the identification of citrullinated protein residues remains challenging owing to the small 1 Da mass change that occurs upon citrullination. Herein, we highlight the progress made so far in the development of pan-PAD and isozyme selective inhibitors as well as the identification of citrullinated proteins and the site-specific incorporation of citrulline into proteins. This article is part of the Theo Murphy meeting issue ‘The virtues and vices of protein citrullination’.

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Section: Selective Protein Arginine Deiminase Inhibitorsmentioning

confidence: 99%

Section: Selective Protein Arginine Deiminase Inhibitorsmentioning

confidence: 99%

Protein citrullination: inhibition, identification and insertion

Barasa,

Thompson

2023

Phil. Trans. R. Soc. B

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“…Moreover, blocking PAD activity using Cl-amidine administration, a pan-PAD inhibitor, caused early mouse embryos to go under cell arrest. More evidence for the critical role of PAD1 induced citrullination during embryonic development was provided using an isozyme-selective inhibitor that blocked histone H3 citrullination in PAD1 expressing HEK293 cells and mouse zygotes [6].…”

Section: Pad1 Maintains Epidermal Integrity and Safeguards Embryonal ...mentioning

confidence: 99%

Insights into peptidylarginine deiminase expression and citrullination pathways

Proost

2022

Trends in Cell Biology

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Exploring Unconventional SAM Analogues To Build Cell‐Potent Bisubstrate Inhibitors for Nicotinamide N‐Methyltransferase

Iyamu¹,

Vilseck

Yadav

et al. 2022

Angewandte Chemie

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Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide and has been associated with various diseases. Herein, we report the first cell-potent NNMT bisubstrate inhibitor II399, demonstrating a K i of 5.9 nM in a biochemical assay and a cellular IC 50 value of 1.9 μM. The inhibition mechanism and cocrystal structure confirmed II399 engages both the substrate and cofactor binding pockets. Computational modeling and binding data reveal a balancing act between enthalpic and entropic components that lead to II399's low nM binding affinity. Notably, II399 is 1 000-fold more selective for NNMT than closely related methyltransferases. We expect that II399 would serve as a valuable probe to elucidate NNMT biology. Furthermore, this strategy provides the first case of introducing unconventional SAM mimics, which can be adopted to develop cell-potent inhibitors for other SAM-dependent methyltransferases.

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Halogen Bonding Increases the Potency and Isozyme Selectivity of Protein Arginine Deiminase 1 Inhibitors

Abstract: Protein Arginine Deiminases (PADs) hydrolyze the side chain of arginine to form citrulline.

Cited by 4 publications

References 30 publications

Protein citrullination: inhibition, identification and insertion

Protein citrullination: inhibition, identification and insertion

Insights into peptidylarginine deiminase expression and citrullination pathways

Exploring Unconventional SAM Analogues To Build Cell‐Potent Bisubstrate Inhibitors for Nicotinamide N‐Methyltransferase

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