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苏拉明可强烈抑制 THP1 细胞中的环鸟苷酸-腺苷酸合成酶（cGAS），从而调节 IFN-β 水平。

Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels.

机构信息

Purdue Institute for Drug Discovery, Department of Chemistry, Purdue Institute of Inflammation, Immunology & Infectious Disease, Purdue University, West Lafayette, IN 47907, USA.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.

出版信息

Future Med Chem. 2018 Jun 1;10(11):1301-1317. doi: 10.4155/fmc-2017-0322. Epub 2018 Mar 21.

DOI:10.4155/fmc-2017-0322

PMID:29558821

Abstract

AIM

Persistent activation of STING pathway is the basis for several autoimmune diseases. STING is activated by cGAMP, which is produced by cGAS in the presence of DNA. Results/methodology: HPLC-based medium throughput screening for inhibitors of cGAS identified suramin as a potent inhibitor. Unlike other reported cGAS inhibitors, which bind to the ATP/GTP binding site, suramin displaced the bound DNA from cGAS. Addition of suramin to THP1 cells reduced the levels of IFN-β mRNA and protein. Suramin did not inhibit lipopolysaccharide- or Pam3CSK4-induced IL-6 mRNA expression.

CONCLUSION

Suramin inhibits STING pathway via the inhibition of cGAS enzymatic activity. Suramin or analogs thereof that displace DNA from cGAS could be used as anti-inflammatory drugs.

摘要

目的

STING 通路的持续激活是几种自身免疫性疾病的基础。STING 由 cGAS 在 DNA 存在的情况下产生的 cGAMP 激活。

结果/方法：基于 HPLC 的中等通量筛选 cGAS 的抑制剂，发现苏拉明是一种有效的抑制剂。与其他报道的 cGAS 抑制剂不同，苏拉明结合在 ATP/GTP 结合位点上，而是将结合的 DNA 从 cGAS 上置换下来。将苏拉明添加到 THP1 细胞中，降低了 IFN-β mRNA 和蛋白的水平。苏拉明不抑制脂多糖或 Pam3CSK4 诱导的 IL-6 mRNA 表达。