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
Despite numerous studies, the role of separate domains of TLR4 in the regulation of receptor activation is poorly understood. Authors proved that TLR4 represents a receptor with low threshold of activation, which can be rapidly activated by the release of inhibition exerted by its ectodomain. This is important for the sensitivity of TLR4 to activation by different agonists. TLR4 ectodomain has multiple roles in enabling ligand regulated activation, providing proper localization, while serving as an inhibitor to prevent spontaneous, ligand-independent dimerization.
COBISS.SI-ID: 4652570