Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4.
Alleviation of arthritis through prevention of neutrophil extracellular traps by an orally available inhibitor of protein arginine deiminase 4.
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DOI：
10.1038/s41598-023-30246-2
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发表时间：
2023-02-23
影响因子：
4.6
通讯作者：
Sivanandhan, Dhanalakshmi
中科院分区：
文献类型：
--
作者：
Gajendran, Chandru;Fukui, Shoichi;Sadhu, Naveen M.;Zainuddin, Mohammed;Rajagopal, Sridharan;Gosu, Ramachandraiah;Gutch, Sarah;Fukui, Saeko;Sheehy, Casey E.;Chu, Long;Vishwakarma, Santosh;Jeyaraj, D. A.;Hallur, Gurulingappa;Wagner, Denisa D.;Sivanandhan, Dhanalakshmi
蛋白质精氨酸脱亚胺酶（PAD）4是催化蛋白质的瓜氨酸化的酶，其在自身免疫性疾病中的作用已经通过小鼠的临床遗传学和基因敲除研究确定。此外，对PAD 4缺陷小鼠的研究表明，PAD 4缺陷不会导致感染或免疫抑制增加，这使得PAD 4成为自身免疫和炎症性疾病的有吸引力的治疗靶点。PAD 4具有促进染色质去凝聚和中性粒细胞胞外陷阱（NETs）形成的关键酶促作用，其与许多免疫介导的病理状况相关。在这里，我们提出了一个非共价的PAD 4抑制剂JBI-589具有高的PAD 4异构体的选择性，并描绘了其结合模式，在2.88纳米分辨率的X射线晶体学。我们证实了其在体外抑制NET形成的有效性。此外，通过使用人类类风湿性关节炎（RA）的两种小鼠关节炎模型，临床上众所周知的与PAD 4相关的疾病，我们建立了其体内疗效。这些结果表明，JBI-589将有益于PAD 4和NET相关的病理状况。
Protein arginine deiminases (PAD) 4 is an enzyme that catalyzes citrullination of protein and its role in autoimmune diseases has been established through clinical genetics and gene knock out studies in mice. Further, studies with PAD4 – 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 associated with a number 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 Å 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 in vivo. These results suggest that JBI-589 would be beneficial for both PAD4 and NET-associated pathological conditions.
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影响因子：
7.3
作者：
Liu Y;Carmona-Rivera C;Moore E;Seto NL;Knight JS;Pryor M;Yang ZH;Hemmers S;Remaley AT;Mowen KA;Kaplan MJ
通讯作者：
Kaplan MJ
影响因子：
13.6
作者：
Ghari F;Quirke AM;Munro S;Kawalkowska J;Picaud S;McGouran J;Subramanian V;Muth A;Williams R;Kessler B;Thompson PR;Fillipakopoulos P;Knapp S;Venables PJ;La Thangue NB
通讯作者：
La Thangue NB
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
14.8
作者：
Lewis, Huw D.;Liddle, John;Coote, Jim E.;Atkinson, Stephen J.;Barker, Michael D.;Bax, Benjamin D.;Bicker, Kevin L.;Bingham, Ryan P.;Campbell, Matthew;Chen, Yu Hua;Chung, Chun-Wa;Craggs, Peter D.;Davis, Rob P.;Eberhard, Dirk;Joberty, Gerard;Lind, Kenneth E.;Locke, Kelly;Maller, Claire;Martinod, Kimberly;Patten, Chris;Polyakova, Oxana;Rise, Cecil E.;Ruediger, Martin;Sheppard, Robert J.;Slade, Daniel J.;Thomas, Pamela;Thorpe, Jim;Yao, Gang;Drewes, Gerard;Wagner, Denisa D.;Thompson, Paul R.;Prinjha, Rab K.;Wilson, David M.
通讯作者：
Wilson, David M.
影响因子：
8
作者：
Liu, Yudong;Lightfoot, Yaima L.;Kaplan, Mariana J.
通讯作者：
Kaplan, Mariana J.