Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation.
Development of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation.
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靶向蛋白-DNA相互作用和相分离的CGA的环肽抑制剂的发展。
DOI：
10.1038/s41467-023-41892-5
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发表时间：
2023-10-02
影响因子：
16.6
通讯作者：
Quan, Junmin
中科院分区：
文献类型：
--
作者：
Wang, Xiaoquan;Wang, Youqiao;Cao, Anqi;Luo, Qinhong;Chen, Daoyuan;Zhao, Weiqi;Xu, Jun;Li, Qinkai;Bu, Xianzhang;Quan, Junmin
环状GMP-AMP合成酶(CGAS)是异常胞浆DNA的重要感受器，在入侵病原体和细胞应激时启动天然免疫，被认为是治疗自身免疫性和自身炎症性疾病的潜在药物靶点。在这里，我们报告了一类环肽抑制剂的发现，这类环肽抑制剂是通过体外筛选实验从环肽的集中文库中鉴定出来的。这些环肽与cGAS的DNA结合部位发生特异性结合，阻断dsDNA与cGAS的结合，从而抑制dsDNA诱导的液相缩合和cGAS的激活。在细胞检测中鉴定了一种最佳导联XQ2B的特异性和效价。相应地，XQ2B在体内外抑制单纯疱疹病毒-1(HSV-1)诱导的抗病毒免疫反应，增强HSV-1感染。此外，XQ2B显著抑制TREX1-/-小鼠原代巨噬细胞中I型干扰素和促炎细胞因子水平的升高，以及TREX1-/-小鼠的全身性炎症。XQ2B是一种针对蛋白质-DNA相互作用和相分离的特异性cGAS抑制剂，为cGAS依赖型炎症性疾病的治疗提供了一个支架。环状GMP-AMP合成酶(CGAS)在调节细胞炎症中起关键作用。在此，作者报道了一类针对蛋白质DNA相互作用和相分离的cGAS环肽抑制剂。
Cyclic GMP-AMP synthase (cGAS) is an essential sensor of aberrant cytosolic DNA for initiating innate immunity upon invading pathogens and cellular stress, which is considered as a potential drug target for autoimmune and autoinflammatory diseases. Here, we report the discovery of a class of cyclopeptide inhibitors of cGAS identified by an in vitro screening assay from a focused library of cyclic peptides. These cyclopeptides specifically bind to the DNA binding site of cGAS and block the binding of dsDNA with cGAS, subsequently inhibit dsDNA-induced liquid phase condensation and activation of cGAS. The specificity and potency of one optimal lead XQ2B were characterized in cellular assays. Concordantly, XQ2B inhibited herpes simplex virus-1 (HSV-1)-induced antiviral immune responses and enhanced HSV-1 infection in vitro and in vivo. Furthermore, XQ2B significantly suppressed the elevated levels of type I interferon and proinflammatory cytokines in primary macrophages from Trex1-/- mice and systemic inflammation in Trex1-/- mice. XQ2B represents the specific cGAS inhibitor targeting protein-DNA interaction and phase separation and serves as a scaffold for the development of therapies in the treatment of cGAS-dependent inflammatory diseases. Cyclic GMP-AMP synthase (cGAS) is critical in modulating cellular inflammation. Here, the authors report a class of cyclopeptide inhibitors of cGAS targeting protein DNA interaction and phase separation.
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影响因子：
3.4
作者：
Cardote TA;Ciulli A
通讯作者：
Ciulli A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.4
作者：
Ashrafuzzaman, Md.;Andersen, O. S.;McElhaney, R. N.
通讯作者：
McElhaney, R. N.
影响因子：
32.4
作者：
Gall A;Treuting P;Elkon KB;Loo YM;Gale M Jr;Barber GN;Stetson DB
通讯作者：
Stetson DB
影响因子：
64.8
作者：
Domizio JD;Gulen MF;Saidoune F;Thacker VV;Yatim A;Sharma K;Nass T;Guenova E;Schaller M;Conrad C;Goepfert C;de Leval L;Garnier CV;Berezowska S;Dubois A;Gilliet M;Ablasser A
通讯作者：
Ablasser A