Discovery of a structurally novel, drug-like and potent inhibitor of peptidylarginine deiminase

Ferretti, Patrizia; U, Kin Pong; Vagaska, Barbora; Merchant, Rohan R.; Matthews, Christopher J.; Marson, Charles M.

doi:10.1039/c3md00091e

Cited by 11 publications

(12 citation statements)

References 24 publications

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“… 123 Moreover, the acylguanidine derivative 17 was shown to block PAD3 with an IC 50 of 100 nM. 124 However, given that acylguanidines have a low p K a value, typically several orders of magnitude lower than that of guanidines, and are expected to be poorly suited as arginine substrate mimicking inhibitors, the strong inhibitory activity of 17 needs further validation. Although it was hypothesized that these compounds act as competitive inhibitors, their detailed mode of inhibition has not been studied.…”

Section: Inhibitors Of Arginine Modifying Enzymesmentioning

confidence: 99%

Protein Arginine Methylation and Citrullination in Epigenetic Regulation

2015

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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.

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Section: Inhibitors Of Arginine Modifying Enzymesmentioning

confidence: 99%

Protein Arginine Methylation and Citrullination in Epigenetic Regulation

2015

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“…PADs are also implicated in cancer ( 44 – 46 ), including through regulation of microvesicular (MV) release ( 47 ), which also is related to cerebral hypoxia induced by acute ischemic stroke ( 48 , 49 ). PAD2 is considered the main central nervous system (CNS) isozyme ( 50 ), but PAD3 and PAD4 are also detected in neuronal tissue ( 19 , 51 , 52 ). PAD4 is the only isozyme with a designated nuclear translocation site, but the nuclear translocation of PAD2 and PAD3 has also been reported ( 19 , 43 , 44 , 47 ).…”

Section: Peptidylarginine Deiminasesmentioning

confidence: 99%

“…In the same vein, PAD activity induced by HI insult and LPS stimulation increased neuronal damage following HI insult with beneficial effect of PAD inhibition. This indicates that LPS-induced upregulation of macrophage TNFα and related cytokines may act as upstream signals to PADs and histone deimination in HIE as well as in other forms of brain damage [( 52 ); Figure 2 ].…”

Section: Pads In Epigeneticsmentioning

confidence: 99%

“…The effects observed on changes in histone deimination suggest a role for epigenetic regulation in response to CNS injury, while changes in deimination of cytoskeletal components could affect apoptosis, cell motility, and the ability of injured neurons to regrow axons ( 19 , 43 , 53 ). While the pan-PAD inhibitor Cl-amidine ( 126 ) still remains the most used experimental inhibitor to date, the therapeutic potential and generation of selective PAD inhibitors is receiving ever increasing attention ( 52 , 127 – 131 ).…”

Section: Hypothermia and Pad Inhibition – A Synergistic Treatment Optmentioning

confidence: 99%

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Peptidylarginine Deiminases as Drug Targets in Neonatal Hypoxic–Ischemic Encephalopathy

Lange

2016

Front. Neurol.

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Oxygen deprivation and infection are major causes of perinatal brain injury leading to cerebral palsy and other neurological disabilities. The identification of novel key factors mediating white and gray matter damage are crucial to allow better understanding of the specific contribution of different cell types to the injury processes and pathways for clinical intervention. Recent studies in the Rice–Vannucci mouse model of neonatal hypoxic ischemia (HI) have highlighted novel roles for calcium-regulated peptidylarginine deiminases (PADs) and demonstrated neuroprotective effects of pharmacological PAD inhibition following HI and synergistic infection mimicked by lipopolysaccharide stimulation.

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“…These neurodegenerative iPSC models will be useful functional tools for continuing studies on effects of PAD-mediated EV shedding, and the efficacy of pharmacological modulation of PAD-mediated mechanisms to ameliorate neurodegenerative disease pathologies. While Cl-Am [141] remains the most used experimental inhibitor to date, the therapeutic potential and generation of second generation and selective isozyme-specific PAD inhibitors is receiving ever increasing attention [72,82,[142][143][144][145][146]. Ongoing work aims at dissecting the roles of individual PAD isozymes in EV biogenesis, to identify further deiminated key target proteins, assess the epigenetic impact of histone deimination, and to evaluate disease-specific EV cargo.…”

Section: Discussionmentioning

confidence: 99%

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

Lange¹,

Kholia²,

Kosgodage³

et al. 2017

Preprint

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Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

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Discovery of a structurally novel, drug-like and potent inhibitor of peptidylarginine deiminase

Cited by 11 publications

References 24 publications

Protein Arginine Methylation and Citrullination in Epigenetic Regulation

Protein Arginine Methylation and Citrullination in Epigenetic Regulation

Peptidylarginine Deiminases as Drug Targets in Neonatal Hypoxic–Ischemic Encephalopathy

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

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