we didn't find any specific TLR7 specific antagonist . maximum are dual antagonist of TLR7 and TLR9 antagonist. Is there any specificity on the protein active site? what was the reason for that?
Dear Sourav,
Lamphier M et al. 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. Lamphier M et al. data also confirm an earlier report that this same mechanism may explain inhibition of TLR7 and 9 signaling by hydroxychloroquine (Plaquenil; Sanofi-Aventis, Bridgewater, NJ), 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.
http://www.ncbi.nlm.nih.gov/pubmed/24342772
Hoping this will be helpful,
Rafik
" 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"
The TLR7 and 9 have similar interactions with the inhibitors via their nucleic acids. These interactions are similar for TLR 7 and 9, therefore any inhibitor for TLR7 will be as good as for TLR9.
Rafik
Sourav, I believe there are some oligonucleotide antagonists that are somewhat specific for TLR7 versus TLR9: ODN 2087, 20958, 20959. There is one paper that also mentions 2'OMe RNA as a selective TLR7 antagonist. As for small-molecule inhibitors selective for TLR7, these have been developed but are not yet commercially available.
but we didnot know how they are act? even we doesnot know also if they bind on the TLR7 receptor or the other else. so why the possibilities of discovery of TLR7 antagonist is less than TLR9?
Sourav, sorry not sure what you are asking.
The mechanism by which oligonucleotide antagonists work is probably via competition for the oligonucleotide ligand, although some papers suggest additional mechanisms.
The mechanism by which the small-molecule dual antagonists work, such as the one I published, is concentration in the endosomes and binding to nucleic acids.
The mechanism by which any new TLR7 or 9 antagonist might work has not been studied in detail. I know there is a small-molecule TLR7 antagonist, but I have not heard of a small-molecule TLR9 antagonist being identified, althouhg attempts have been made. That might suggest that small-molecule TLR7 antagonists are easier to obtain ( or it might mean nothing).
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