RT Journal Article
SR Electronic
T1 Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.089821
DO 10.1124/mol.113.089821
A1 Marc Lamphier
A1 Wanjun Zheng
A1 Eicke Latz
A1 Mark Spyvee
A1 Hans Hansen
A1 Jeffrey Rose
A1 Melinda Genest
A1 Hua Yang
A1 Christina Shaffer
A1 Yan Zhao
A1 Yongchun Shen
A1 Carrie Liu
A1 Diana Liu
A1 Thorsten R Mempel
A1 Christopher Rowbottom
A1 Jesse Chow
A1 Natalie C Twine
A1 Melvin Yu
A1 Fabian Gusovsky
A1 Sally T Ishizaka
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/12/16/mol.113.089821.abstract
AB 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.