Recent discoveries significantly improved our understanding of molecular mechanism of endosomal TLRs and their physiological role. Those include recognition of dsRNA through two nucleic acid binding sites of TLR3 ectodomain, activation of TLR9 by phosphodiester backbone of ssDNA, independent of the nucleotide sequence and phosphorothioate modified bonds, and the role of proteolysis in activation of TLR9. There is growing evidence that supports involvement of endosomal TLRs in a number of autoimmune diseases, suggesting a therapeutic potential of immunomodulatory endosomal TLR ligands.
COBISS.SI-ID: 4351258
TLR3 receptor recognizes stranded RNA, which is characteristic for several viruses. We have discovered the RNA binding site at N-terminus. TLR3 dimerization requires binding of RNA to both binding sites. We showed that siRNA comprising 21 bp represents the minimal size of RNA duplex that can bind to both binding sites of TLR3 ectodomain and causes nonspecific interferon production. Those results were presented in several invited lectures (IEIIS Edinburgh 2008, Austrian society of immunology and allergology, Vienna 2010, U.Cambridge, U.Heidelberg).
COBISS.SI-ID: 3954714
We described the application of nucleic acids that activate or inhibit Toll-like receptors TLR3, TLR9, and TLR7 with TLR8 based on results from our group and from the literature. Understanding of the molecular mechanism of activation is essential for the improved drug design.
COBISS.SI-ID: 4121114
In this article in the respected journal in the field of immunology, we reported the discovery of the mechanism of action antimalarials that are similar to quinacrin. In contrast to the prevailing opinion in literature we discovered that these inhibitors at therapeutic concentrations do not prevent endosomal acidification but directly bind to the nucleic acid. In this way they prevent the nucleic acid to activate endosomal TLRs such as TLR3, TLR7 and TLR9. The result is a significant particularly for the improvement of treatment of diseases characterized by activation of TLR9, 7, 8 and 3.
COBISS.SI-ID: 2971761