瓜氨酸化
中性粒细胞胞外陷阱
类风湿性关节炎
关节炎
免疫系统
细胞外
体内
免疫学
炎症
染色质
自身免疫性疾病
精氨酸
化学
瓜氨酸
生物
医学
生物化学
基因
氨基酸
抗体
遗传学
作者
Chandru Gajendran,Shoichi Fukui,Naveen M Sadhu,Mohammed Zainuddin,Sridharan Rajagopal,Ramachandraiah Gosu,Sarah Gutch,Saeko Fukui,Casey E Sheehy,Long Chu,Santosh Vishwakarma,D A Jeyaraj,Gurulingappa Hallur,Denisa D. Wagner,Dhanalakshmi Sivanandhan
标识
DOI:10.1038/s41598-023-30246-2
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI