Peptidylarginine deiminases 4 as a promising target in drug discovery

Yang, Chao; Dong, Zhenzhen; Zhang, Jing; Teng, Dehong; Luo, Xinzhi; Li, Dan; Zhou, Yingtang

doi:10.1016/j.ejmech.2021.113840

Cited by 21 publications

(16 citation statements)

References 130 publications

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“…These results agree with previous observations reporting that PADI4 inhibition results in different outcomes in multiple cancer cell lines (Yuzhalin, 2019), besides its different expression among several cell lines, as we have recently shown . Then, all in all, those findings suggest that the inhibitory effect of GSK484 may have different effects among the cell lines (Duan et al, 2016;Stadler et al, 2013;Yuzhalin et al, 2018;Zhang et al, 2021). Altogether, our experiments showed that, in the presence of GSK484, the binding between MDM2 and PADI4 was hampered (Figures 2 and S3).…”

Section: Inhibition Of Padi4 In Cellulo Resulted In a Decrease Of Pad...mentioning

confidence: 57%

New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4

Araujo‐Abad,

Rizzuti,

Villamarin‐Ortiz

et al. 2023

Protein Science

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PADI4 is one of the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline. MDM2 is an E3 ubiquitin ligase which is crucial for down-regulation of degradation of the tumor suppressor gene p53.Given the relationship between both PADI4 and MDM2 with p53-signaling pathways, we hypothesized they may interact directly, and this interaction could be relevant in the context of cancer. Here, we showed their association in the nucleus and cytosol in several cancer cell lines. Furthermore, binding was hampered in the presence of GSK484, an enzymatic PADI4 inhibitor, suggesting that MDM2 could bind to the active site of PADI4, as confirmed by in silico experiments. In vitro and in silico studies showed that the isolated

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Section: Inhibition Of Padi4 In Cellulo Resulted In a Decrease Of Pad...mentioning

confidence: 57%

New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4

Araujo‐Abad,

Rizzuti,

Villamarin‐Ortiz

et al. 2023

Protein Science

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“…Neutrophils could also exacerbate intestinal inflammation and cause malignancies by producing neutrophil extracellular traps (NETs) (18). NETs are reticular structures that induce the formation of NETs through the conversion of arginine residues to citrulline dependent on peptidyl arginine deiminase type IV (PAD4) (19)(20)(21). Myeloperoxidase (MPO), a heme peroxidase that is mostly kept in the nitrogenophilic granules of neutrophils and produced following the activation of neutrophils (22).…”

Section: Introductionmentioning

confidence: 99%

Identifying neutrophil-associated subtypes in ulcerative colitis and confirming neutrophils promote colitis-associated colorectal cancer

Zhang

Zhang²,

Song³

et al. 2023

Front. Immunol.

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BackgroundUlcerative colitis (UC) is a chronic inflammatory disease of the intestinal mucosa, the incidence of which has increased worldwide. There is still a lack of clear understanding of the pathogenesis of ulcerative colitis that ultimately leads to colitis-associated colorectal cancer.MethodWe download UC transcriptome data from the GEO database and pass the limma package in order to identify differentially expressed genes. Gene Set Enrichment Analysis (GSEA) was used to identify potential biological pathways. We identified immune cells associated with UC by CIBERSORT and Weighted co-expression network analysis (WGCNA). We used validation cohorts and mouse models to verify the expression of the hub genes and the role of neutrophils.ResultWe identified 65 differentially expressed genes in UC samples and healthy controls. GSEA, KEGG, and GO analyses displayed that DEGs were enriched in immune-related pathways. CIBERSORT analysis revealed increased infiltration of neutrophils in UC tissues. The red module, obtained by WGCNA analysis, was considered to be the most relevant module for neutrophils.Based on neutrophil-associated differentially expressed genes, UC patients were classified into two subtypes of neutrophil infiltration. We discovered that the highly neutrophil-infiltrated subtype B of UC patients had a higher risk of developing CAC. Five genes were identified as biomarkers by searching for DEGs between distinct subtypes. Finally, using the mouse model, we determined the expression of these five genes in the control, DSS, and AOM/DSS groups. The degree of neutrophil infiltration in mice and the percentage of MPO and pSTAT3 expression in neutrophils were analyzed by flow cytometry. In the AOM/DSS model, MPO and pSTAT3 expressions were significantly increased.ConclusionsThese findings suggested neutrophils might promote the conversion of UC into CAC. These findings improve our understanding of the pathogenesis of CAC and provide new and more effective insights into the prevention and treatment of CAC.

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“…PAD4 (peptidyl arginine deiminase 4) is a member of a set of five closely related proteins (PAD1–4 and PAD6) that carry out post translational modifications of peptidyl arginine residues via calcium dependent deimination of the positively charged residues to give neutral citrulline residues. , While the family of proteins are widely distributed throughout the body and are involved in many important physiological and pathological processes, PAD4 is most highly expressed in in bone marrow, lymphoid tissues, and blood and plays a key role in NETosis. , …”

Section: Proteins Adopting Novel Conformationsmentioning

confidence: 99%

“…52,53 While the family of proteins are widely distributed throughout the body and are involved in many important physiological and pathological processes, PAD4 is most highly expressed in in bone marrow, lymphoid tissues, and blood and plays a key role in NETosis. 54,55 Early work on substrate analogues identified halo amidines 6 and 7 as irreversible inhibitors of PAD4 (Figure 3a), with modest activity and poor selectivity against other peptidyl arginine deiminases. 56,57 However, in 2015, GlaxoSmithKline (GSK) reported a novel structural class of selective PAD4 inhibitors that were active against the calcium deficient protein.…”

Section: T H Imentioning

confidence: 99%

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

Collie,

Clark,

Keefe

et al. 2024

J. Med. Chem.

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The DNA-encoded library (DEL) discovery platform has emerged as a powerful technology for hit identification in recent years. It has become one of the major parallel workstreams for small molecule drug discovery along with other strategies such as HTS and data mining. For many researchers working in the DEL field, it has become increasingly evident that many hits and leads discovered via DEL screening bind to target proteins with unique and unprecedented binding modes. This Perspective is our attempt to analyze reports of DEL screening with the purpose of providing a rigorous and useful account of the binding modes observed for DEL-derived ligands with a focus on binding mode novelty. ■ SIGNIFICANCEScreening DNA-encoded libraries (DELs) of small molecules has recently become one of the main technologies employed for discovering potential new drugs. Here, we analyze and discuss recent published DEL screens performed against important clinical molecular targets. Notable trends observed, including an apparent tendency for inhibitors from DEL screens to be highly selective and to adopt novel binding modes, are highlighted and discussed alongside the current state of the field and future considerations.

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Peptidylarginine deiminases 4 as a promising target in drug discovery

Cited by 21 publications

References 130 publications

New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4

New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4

Identifying neutrophil-associated subtypes in ulcerative colitis and confirming neutrophils promote colitis-associated colorectal cancer

Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein–Ligand Interactions and High Selectivity

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