TY - JOUR T1 - Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.089821 SP - mol.113.089821 AU - Marc Lamphier AU - Wanjun Zheng AU - Eicke Latz AU - Mark Spyvee AU - Hans Hansen AU - Jeffrey Rose AU - Melinda Genest AU - Hua Yang AU - Christina Shaffer AU - Yan Zhao AU - Yongchun Shen AU - Carrie Liu AU - Diana Liu AU - Thorsten R Mempel AU - Christopher Rowbottom AU - Jesse Chow AU - Natalie C Twine AU - Melvin Yu AU - Fabian Gusovsky AU - Sally T Ishizaka Y1 - 2013/01/01 UR - http://molpharm.aspetjournals.org/content/early/2013/12/16/mol.113.089821.abstract N2 - The discovery that circulating nucleic acid-containing complexes in the serum of autoimmune lupus patients can stimulate B cells and plasmacytoid dendritic cells via Toll-like receptors 7 and 9 suggested that agents that block these receptors might be useful therapeutics. We identified two compounds, AT791 and E6446, that inhibit TLR7 and 9 signaling in a variety of human and mouse cell types, and inhibit DNA - TLR9 interaction in vitro. When administered to mice, these compounds suppress responses to challenge doses of CpG-containing DNA, which stimulates TLR9. When given chronically in spontaneous mouse lupus models, E6446 slowed development of circulating anti-nuclear antibodies and had a modest effect on anti-double stranded DNA (dsDNA) titers, but showed no observable impact on proteinuria or mortality. We discovered that the ability of AT791 and E6446 to inhibit TLR7 and 9 signaling depends on two properties: weak interaction with nucleic acids and high accumulation in the intracellular acidic compartments where TLR7 and 9 reside. Binding of the compounds to DNA prevents DNA - TLR9 interaction in vitro and modulates signaling in vivo. Our data also confirms an earlier report that this same mechanism may explain inhibition of TLR7 and 9 signaling by hydroxychloroquine (Plaquenil), a drug commonly prescribed to treat lupus. Thus, very different structural classes of molecules can inhibit endosomal TLRs by essentially identical mechanisms of action, suggesting a general mechanism for targeting this group of TLRs. ER -