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Further, studies with PAD4 \u2013 deficient mice have shown that PAD4 deficiency does not lead to increased infection or immune suppression, which makes PAD4 an attractive therapeutic target for auto-immune and inflammatory diseases. PAD4 has critical enzymatic role of promoting chromatin decondensation and neutrophil extracellular traps (NETs) formation that is\u00a0associated with a\u00a0number of immune-mediated pathological conditions. Here, we present a non-covalent PAD4 inhibitor JBI-589 with high PAD4 isoform selectivity and delineated its binding mode at 2.88\u00a0\u00c5 resolution by X-ray crystallography. We confirmed its effectiveness in inhibiting NET formation in vitro. Additionally, by using two mouse arthritis models for human rheumatoid arthritis (RA), the well-known disease associated with PAD4 clinically, we established its efficacy\u00a0in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.<\/jats:p>","DOI":"10.1038\/s41598-023-30246-2","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T10:02:29Z","timestamp":1677146549000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4"],"prefix":"10.1038","volume":"13","author":[{"given":"Chandru","family":"Gajendran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoichi","family":"Fukui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveen M.","family":"Sadhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Zainuddin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridharan","family":"Rajagopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramachandraiah","family":"Gosu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Gutch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeko","family":"Fukui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey E.","family":"Sheehy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Vishwakarma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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GH, J.D.A and SV are employees of Jubilant Biosys Ltd. The specific roles of all the authors are articulated in the \u2018author contributions\u2019 section. we confirm that \u201cThis does not alter our adherence to Scientific Reports policies on sharing data and materials.\u201d D.S and S.R. are inventors on one and two patents respectively; covering JBI-589 and related compounds and their use in the treatment of disease\/disorder mediated by PAD4. The other authors mentioned in this paper declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3189"}}