Peptidylarginine deiminases 4 as a promising target in drug discovery
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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2023, Biochimica et Biophysica Acta - Proteins and ProteomicsCitation 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].
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These authors contributed equally to this work.