Modi Wang1,2, Moloud A Sooreshjani1,2, Clinton Mikek1,2, Clement Opoku-Temeng1,3, Herman O Sintim1,2. 1. Purdue Institute for Drug Discovery, Department of Chemistry, Purdue Institute of Inflammation, Immunology & Infectious Disease, Purdue University, West Lafayette, IN 47907, USA. 2. Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. 3. Biochemistry Graduate Program, University of Maryland, College Park, MD 20742, USA.
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.
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.
Authors: Roxane Valentin; Christophe Wong; Arwaf S Alharbi; Solène Pradeloux; Makala P Morros; Kim A Lennox; Julia I Ellyard; Aurélie J Garcin; Tomalika R Ullah; Gina D Kusuma; Geneviève Pépin; Hong-Mei Li; Jaclyn S Pearson; Jonathan Ferrand; Rebecca Lim; Rakesh N Veedu; Eric F Morand; Carola G Vinuesa; Mark A Behlke; Michael P Gantier Journal: Nucleic Acids Res Date: 2021-06-21 Impact factor: 16.971
Authors: Carolyn N Paulson; Kristen John; Ryan M Baxley; Fredy Kurniawan; Kayo Orellana; Rawle Francis; Alexandra Sobeck; Brandt F Eichman; Walter J Chazin; Hideki Aihara; Gunda I Georg; Jon E Hawkinson; Anja-Katrin Bielinsky Journal: Open Biol Date: 2019-08-14 Impact factor: 6.411