Peptidylarginine deiminases 4 as a promising target in drug discovery

doi:10.1016/j.ejmech.2021.113840

European Journal of Medicinal Chemistry

Volume 226, 15 December 2021, 113840

https://doi.org/10.1016/j.ejmech.2021.113840 Get rights and content

Highlights

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PAD4 inhibition is a promising method for diagnosis and treatment of diseases.
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Detailed pathophysiology functions of PAD4 is described.
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More research and clinical data are needed to understand the mechanism of PAD4 in diseases.

Abstract

Peptidylarginine deaminase 4 (PAD4) is a crucial post-translational modifying enzyme catalyzing the conversion of arginine into citrulline residues, and mediating the formation of neutrophil extracellular traps (NETs). PAD4 plays a vital role in the occurrence and development of cardiovascular diseases, autoimmune diseases, and various tumors. Therefore, PAD4 is considered as a promising drug target for disease diagnosis and treatment. More and more efforts are devoted to developing highly efficient and selective PAD4 inhibitors via high-throughput screening, structure-based drug design and structure-activity relationship study. This article outlined the physiological and pathological functions of PAD4, and corresponding representative small molecule inhibitors reported in recent years.

Graphical abstract

Introduction

PAD4 is one of the most important enzymes in the process of protein post-translational modification, which converts arginine residues into citrulline residues in polypeptide chains in the presence of calcium ions. PAD4 regulates gene expression through citrullinated histone and nucleolar phosphoprotein, and participates in various biological processes, such as apoptosis, cell differentiation [[1], [2], [3], [4]]. PAD4 was first discovered as a functional protein in leukemia [[3], [4], [5]]. While studies in the past decade have found that PAD4 directly or indirectly takes part in the pathogenesis of autoimmune diseases, tumor metastasis, immune escape, and cardiovascular diseases by citrullination and/or NETs [[6], [7], [8]]. Therefore, PAD4 inhibitors can be employed as a new strategy for disease treatment, particularly cardiovascular diseases, autoimmune diseases, neurodegenerative diseases and tumors.

Section snippets

Structure and biological function of PAD4

Human PAD4 is composed of 663 amino acids, which was firstly discovered in human myeloid leukemia HL-60 cells (Fig. 1A and B) [1,5]. PAD4 has unique N- and C-terminal domains, and the N-domain is further differentiated into two immunoglobulin-like subdomains (Fig. 1C). Subdomain 1 (residues 1–118) has 2 calcium binding sites, while subdomain 2 (residues 119–300) possesses three Ca²⁺ binding sites. The C-domain includes 5 ββαβ modular structures, which are arranged circularly in a

PAD4 in NETs formation

NETs have attracted more attention since discovered in 2004. NETs can be detected whether they are exposed to pathogens or in the sterile environment of autoimmune diseases. NETs generate/capture self-antigens and aggravate the inflammatory response, affecting the progress of autoimmune diseases [45]. The generation and function of NETs are adjusted by a variety of enzymes, including myeloperoxidase, NADPH oxidase, Rac2 of the Rho family, and PAD4 [46].

PAD4 is mainly distributed in macrophages,

PAD4 in immune diseases

Rheumatoid arthritis (RA) is a complex autoimmune disease mainly induced by genetic and environmental factors, with a worldwide prevalence of 0.5–1% [58]. Based on the studies of serology, genetics and biochemistry, it has proved that the disorder of PAD4 activity is closely related to the occurrence and development of RA [[59], [60], [61]]. PAD4 involves in the pathogenesis of RA through citrullination [62]. As for RA pathogenesis, the subcellular localization of PADs is noteworthy, because

Small non-peptidic inhibitors of PAD4

Considering the important role of PAD4-mediated NETs formation and citrullination in various physiological and pathological processes, some inhibitors have been developing to target PAD4. Here, we listed some representative latest small molecule inhibitors of PAD4 to explain the potential value of PAD4 in the treatment of diseases, laying foundation for the development of new efficient PAD4 drugs (Fig. 4 and Table 1).

In 2006, Thompson et al. designed N-α-benzoyl-N⁵-(2-fluoro-1-iminoethyl)-l

Conclusion and prospect

More and more evidence shows that epigenetic changes lead to the occurrence and development of diseases, especially abnormal DNA methylation and histone modifications including acetylation and deacetylation. PAD4-mediated post-translational citrullination is involved in the expression and regulation of many regulatory factors, and is closely related to pathophysiological processes such as injury, inflammation, reproductive development, and aging [[154], [155], [156], [157], [158]]. It is

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This work is financially supported by Start-Up Research Funding from Zhejiang Ocean University (14164060216065), China Postdoctoral Science Foundation (2019M663456 and 2019TQ0044), Xinglin Scholar Research Promotion Project of Chengdu University of TCM (BSH2019008), Sichuan Province Science and technology innovation seedling project (2020091), and Open Research Fund of Chengdu University of Traditional Chinese Medicine Key Laboratory of Systematic Research of Distinctive Chinese Medicine

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Screening of natural inhibitors against peptidyl arginine deiminase 4 from herbal extracts by a high-performance liquid chromatography ultraviolet-visible based method
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Peptidyl arginine deiminase 4 (PAD4) is an important biocatalytic enzymes involved in the conversion of protein arginine to citrulline, its dysregulation has a great impact on many physiological processes. Recently, PAD4 has emerged as a potential therapeutic target for the treatment of various diseases including rheumatoid arthritis (RA). Traditional Chinese Medicines (TCMs), also known as herbal plants, have gained great attention by the scientific community due to their good therapeutic performance and far fewer side effects observed in the clinical treatment. However, limited researches have been reported to screen natural PAD4 inhibitors from herbal plants. The color developing reagent (COLDER) or fluorescence based methods have been widely used in PAD4 activity assay and inhibitor screening. However, both methods measure the overall absorbance or fluorescence in the reaction solution, which are easy to be affected by the background interference due to colorful extracts from herbal plants. In this study, a simple, and robust high-performance liquid chromatography ultraviolet-visible (HPLC-UV) based method was developed to determine PAD4 activity. The proposed strategy was established based on COLDER principle, while used hydrophilic l-arginine instead of hydrophobic N-benzoyl-l-arginine ethyl ester (BAEE) as a new substrate to determine PAD4 inhibition activity of herbal extracts. The herbal extracts and PAD4 generated hydrophobic l-citrulline were successfully separated by the HPLC, and the developed method was optimized and validated with a known PAD4 inhibitor (GSK484) in comparison with COLDER assay. The IC₅₀ value of GSK484 measured by HPLC-UV method was 153 nM, and the detection limit of the citrulline was 0.5 nmol, respectively, with a linear range of 0.5 nmol to 20 nmol. The IC₅₀ value of the HPLC-UV method was improved by nearly three times compared with COLDER assay (527 nM), and the results indicated the reliability of PAD4 inhibition via HPLC-UV method. The inhibitory effect against PAD4 were fast and accurately screened for the twenty-four extracts from eight herbs. Among them, Ephedra Herba extracts showed significant inhibitory activity against the PAD4 with the IC₅₀ values of three extracts (ethanol, ethyl acetate and water) ranging from 29.11 μg/mL to 41.36 μg/mL, which may help researchers to discover novel natural compounds holding high PAD4 inhibition activity.
Impact of GSK199 and GSK106 binding on protein arginine deiminase IV stability and flexibility: A computational approach
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Protein arginine deiminase IV (PAD4) is a potential target for diseases including rheumatoid arthritis and cancers. Currently, GSK199 is a potent, selective yet reversible PAD4 inhibitor. Its derivative, GSK106, on the other hand, was reported as an inactive compound when tested against PAD4 assay. Although they had similar skeleton, their impact towards PAD4 structural and flexibility is unknown. In order to fill the research gap, the impact of GSK199 and GSK106 binding towards PAD4 stability and flexibility is investigated via a combination of computational methods. Molecular docking indicates that GSK199 and GSK106 are capable to bind at PAD4 pocket by using its back door with −10.6 kcal/mol and −9.6 kcal/mol, respectively. The simulations of both complexes were stable throughout 100 ns. The structure of PAD4 exhibited a tighter packing in the presence of GSK106 compared to GSK199. The RMSF analysis demonstrates significant changes between the PAD4-GSK199 and PAD4-GSK106 simulations in the regions containing residues 136, 160, 220, 438, and 606. The Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis shows a marked difference in binding free energies, with −11.339 kcal/mol for the PAD4-GSK199 complex and 1.063 kcal/mol for the PAD4-GSK106 complex. The hydrogen bond analysis revealed that the GSK199 and GSK106 binding to PAD4 are assisted by six hydrogen bonds and three hydrogen bonds, respectively. The visualisation of the MD simulations revealed that GSK199 remained in the PAD4 pocket, whereas GSK106 shifted away from the catalytic site. Meanwhile, molecular dockings of benzoyl arginine amide (BAEE) substrate have shown that BAEE is able to bind to PAD4 catalytic site when GSK106 was present but not when GSK199 occupied the site. Overall, combination of computational approaches successfully described the behaviour of binding pocket of PAD4 structure in the presence of the active and inactive compounds.
Post-translational modifications of histone and non-histone proteins in epigenetic regulation and translational applications in alcohol-associated liver disease: Challenges and research opportunities
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Epigenetic regulation is a process that takes place through adaptive cellular pathways influenced by environmental factors and metabolic changes to modulate gene activity with heritable phenotypic variations without altering the DNA sequences of many target genes. Epigenetic regulation can be facilitated by diverse mechanisms: many different types of post-translational modifications (PTMs) of histone and non-histone nuclear proteins, DNA methylation, altered levels of noncoding RNAs, incorporation of histone variants, nucleosomal positioning, chromatin remodeling, etc. These factors modulate chromatin structure and stability with or without the involvement of metabolic products, depending on the cellular context of target cells or environmental stimuli, such as intake of alcohol (ethanol) or Western-style high-fat diets. Alterations of epigenetics have been actively studied, since they are frequently associated with multiple disease states. Consequently, explorations of epigenetic regulation have recently shed light on the pathogenesis and progression of alcohol-associated disorders. In this review, we highlight the roles of various types of PTMs, including less-characterized modifications of nuclear histone and non-histone proteins, in the epigenetic regulation of alcohol-associated liver disease (ALD) and other disorders. We also describe challenges in characterizing specific PTMs and suggest future opportunities for basic and translational research to prevent or treat ALD and many other disease states.
The intrinsically disordered, epigenetic factor RYBP binds to the citrullinating enzyme PADI4 in cancer cells
2023, International Journal of Biological Macromolecules
RYBP (Ring1 and YY 1 binding protein) is a multifunctional, intrinsically disordered protein (IDP), best described as a transcriptional regulator. It exhibits a ubiquitin-binding functionality, binds to other transcription factors, and has a key role during embryonic development. RYBP, which folds upon binding to DNA, has a Zn-finger domain at its N-terminal region. By contrast, PADI4 is a well-folded protein and it is one the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline. As both proteins intervene in signaling pathways related to cancer development and are found in the same localizations within the cell, we hypothesized they may interact. We observed their association in the nucleus and cytosol in several cancer cell lines, by using immunofluorescence (IF) and proximity ligation assays (PLAs). Binding also occurred in vitro, as measured by isothermal titration calorimetry (ITC) and fluorescence, with a low micromolar affinity (~1 μM). AlphaFold2-multimer (AF2) results indicate that PADI4's catalytic domain interacts with the Arg53 of RYBP docking into its active site. As RYBP sensitizes cells to PARP (Poly (ADP-ribose) polymerase) inhibitors, we applied them in combination with an enzymatic inhibitor of PADI4 observing a change in cell proliferation, and the hampering of the interaction of both proteins. This study unveils for the first time the possible citrullination of an IDP, and suggests that this new interaction, whether it involves or not citrullination of RYBP, might have implications in cancer development and progression.
Intrinsically Disordered Chromatin Protein NUPR1 Binds to the Enzyme PADI4
2023, Journal of Molecular Biology
The nuclear protein 1 (NUPR1) is an intrinsically disordered protein involved in stress-mediated cellular conditions. Its paralogue nuclear protein 1-like (NUPR1L) is p53-regulated, and its expression down-regulates that of the NUPR1 gene. Peptidyl-arginine deiminase 4 (PADI4) is an isoform of a family of enzymes catalyzing arginine to citrulline conversion; it is also involved in stress-mediated cellular conditions. We characterized the interaction between NUPR1 and PADI4 in vitro, in silico, and in cellulo. The interaction of NUPR1 and PADI4 occurred with a dissociation constant of 18 ± 6 μM. The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch surrounding the key residue Ala33, as pinpointed by: (i) computational results; and, (ii) site-directed mutagenesis of residues of NUPR1. The association between PADI4 and wild-type NUPR1 was also assessed in cellulo by using proximity ligation assays (PLAs) and immunofluorescence (IF), and it occurred mainly in the nucleus. Moreover, binding between NUPR1L and PADI4 also occurred in vitro with an affinity similar to that of NUPR1. Molecular modelling provided information on the binding hot spot for PADI4. This is an example of a disordered partner of PADI4, whereas its other known interacting proteins are well-folded. Altogether, our results suggest that the NUPR1/PADI4 complex could have crucial functions in modulating DNA-repair, favoring metastasis, or facilitating citrullination of other proteins.
The armadillo-repeat domain of Plakophilin 1 binds to human enzyme PADI4
2023, Biochimica et Biophysica Acta - Proteins and Proteomics
Citation Excerpt :
An increase of the enzymatic activity is also observed for several PADI4 haplotype mutants during the apoptosis occurring via the mitochondrial pathway [16]. Furthermore, PADI4 is involved in the p53-gene expression, and that of other p53 target-genes [15,19,20]. We have recently shown that PADI4 is a dimeric protein expressed in glioblastoma, pancreatic adenocarcinoma and colon cancer [21], and that it binds to importin α3 (Impα3), a member of the armadillo (ARM) repeat-containing family of proteins, to allow its translocation into the cell nucleus [22].
Plakophilin 1 (PKP1), a member of the armadillo repeat family of proteins, is a key structural component of cell-cell adhesion scaffolds, although it can also be found in other cell locations, including the cytoplasm and the nucleus. PADI4 (peptidyl-arginine deiminase 4) is one of the human isoforms of a family of enzymes engaged in the conversion of arginine to citrulline, and is present in monocytes, macrophages, granulocytes, and in several types of cancer cells. It is the only family member observed both within the nucleus and the cytoplasm under ordinary conditions. We studied the binding of the armadillo domain of PKP1 (ARM-PKP1) with PADI4, by using several biophysical methods, namely fluorescence, far-ultraviolet (far-UV) circular dichroism (CD), isothermal titration calorimetry (ITC), and molecular simulations; furthermore, binding was also tested by Western-blot (WB) analyses. Our results show that there was binding between the two proteins, with a dissociation constant in the low micromolar range (∼ 1 μM). Molecular modelling provided additional information on the possible structure of the binding complex, and especially on the binding hot-spot predicted for PADI4. This is the first time that the interaction between these two proteins has been described and studied. Our findings could be of importance to understand the development of tumors, where PKP1 and PADI4 are involved. Moreover, our findings pave the way to describe the formation of neutrophil extracellular traps (NETs), whose construction is modulated by PADI4, and which mediate the proteolysis of cell-cell junctions where PKP1 intervenes.

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¹: These authors contributed equally to this work.

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Peptidylarginine deiminases 4 as a promising target in drug discovery

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Structure and biological function of PAD4

PAD4 in NETs formation

PAD4 in immune diseases

Small non-peptidic inhibitors of PAD4

Conclusion and prospect

Declaration of competing interest

Acknowledgement

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PAD4 inhibitors: potential sensitizers of tumour cells to TRAIL-induced apoptosis

Bioscience Horizons: Int. J. Stud. Res.

A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells

Oncotarget

A novel role for protein arginine deiminase 4 in pluripotency: the emerging role of citrullinated histone H1 in cellular programming

Bioessays

At the Bedside: neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases

J. Leukoc. Biol.

Therapeutic targeting of neutrophil extracellular traps in atherogenic inflammation

Thromb. Haemostasis

Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors

Mol. Carcinog.

Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4

Proc. Natl. Acad. Sci. U. S. A.

Probing the roles of calcium-binding sites during the folding of human peptidylarginine deiminase 4

Sci. Rep.

Structural basis for Ca(2+)-induced activation of human PAD4

Nat. Struct. Mol. Biol.

Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination

Proc. Natl. Acad. Sci. U. S. A.

The human host-defense peptide cathelicidin LL-37 is a nanomolar inhibitor of amyloid self-assembly of islet amyloid polypeptide (IAPP)

Angew Chem. Int. Ed. Engl.

Citrullination alters the antiviral and immunomodulatory activities of the human cathelicidin LL-37 during rhinovirus infection

Front. Immunol.

Peptidylarginine deiminases present in the airways during tobacco smoking and inflammation can citrullinate the host defense peptide LL-37, resulting in altered activities

Am. J. Respir. Cell Mol. Biol.

Citrullination-resistant LL-37 is a potent antimicrobial agent in the inflammatory environment high in arginine deiminase activity

Int. J. Mol. Sci.

Citrullination and proteolytic processing of chemokines by Porphyromonas gingivalis

Infect. Immun.

Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation

J. Exp. Med.

Peptidylarginine deiminases: physiological function, interaction with chemokines and role in pathology

Drug Discov. Today Technol.

A novel role for protein arginine deiminase 4 in pluripotency: the emerging role of citrullinated histone H1 in cellular programming

Bioessays

Pluripotency: citrullination unravels stem cells

Nat. Chem. Biol.

Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors

ACS Chem. Biol.

The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis

Arthritis Rheum.

miR-155: an ancient regulator of the immune system

Immunol. Rev.

MiR-155 regulates PAD4-dependent formation of neutrophil extracellular traps

Front. Immunol.

Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke

Nat. Commun.