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

• Published in: Future medicinal chemistry 2018-06, Vol.10 (11), p.1301-1317
• Main Authors: Wang, Modi, Sooreshjani, Moloud A, Mikek, Clinton, Opoku-Temeng, Clement, Sintim, Herman O
• Format: Article
• Language: English
• Subjects: 2′,3′-cGAMP; Anti-Inflammatory Agents - pharmacology; Autoimmune Diseases - drug therapy; autoinflammatory disease; cGAS; Enzyme Inhibitors - pharmacology; Gene Expression Regulation; Humans; Interferon-beta - genetics; Interferon-beta - metabolism; Membrane Proteins - drug effects; Molecular Structure; Nucleotidyltransferases - antagonists & inhibitors; RNA, Messenger - drug effects; Signal Transduction - drug effects; STING; Structure-Activity Relationship; suramin; Suramin - pharmacology; THP-1 Cells
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2017-0322

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. 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. 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.