Abstract
Microbial as well as endogenous nucleic acids are recognized by a group of endosomal Toll-like receptors TLR3, TLR7, TLR8 and TLR9. Recent discoveries significantly improved our understanding of molecular mechanism of their activation 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. In addition, proteins that chaperone nucleic acids, such as HMGB1 or LL-37, have been described to mediate TLR activation. 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. So far, inhibitory nucleic acids against TLR7, TLR8 and TLR9 as well as small compounds targeting downstream signal transduction of single or several endosomal TLRs have been reported. TLR-targeting drugs have been included in clinical trials as vaccine adjuvants or as therapeutic agents for the treatment of diseases, ranging from cancer, infections, asthma and allergy to autoimmune diseases.
Keywords: Nucleic acids, TLR recognition, mechanism of activation, TLR signaling, immunomodulatory compounds, oligodeoxynucleotides, imidazoquinolines
Current Medicinal Chemistry
Title: Recognition of Nucleic Acids by Toll-Like Receptors and Development of Immunomodulatory Drugs
Volume: 17 Issue: 18
Author(s): A. Kuznik, G. Panter and R. Jerala
Affiliation:
Keywords: Nucleic acids, TLR recognition, mechanism of activation, TLR signaling, immunomodulatory compounds, oligodeoxynucleotides, imidazoquinolines
Abstract: Microbial as well as endogenous nucleic acids are recognized by a group of endosomal Toll-like receptors TLR3, TLR7, TLR8 and TLR9. Recent discoveries significantly improved our understanding of molecular mechanism of their activation 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. In addition, proteins that chaperone nucleic acids, such as HMGB1 or LL-37, have been described to mediate TLR activation. 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. So far, inhibitory nucleic acids against TLR7, TLR8 and TLR9 as well as small compounds targeting downstream signal transduction of single or several endosomal TLRs have been reported. TLR-targeting drugs have been included in clinical trials as vaccine adjuvants or as therapeutic agents for the treatment of diseases, ranging from cancer, infections, asthma and allergy to autoimmune diseases.
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Cite this article as:
Kuznik A., Panter G. and Jerala R., Recognition of Nucleic Acids by Toll-Like Receptors and Development of Immunomodulatory Drugs, Current Medicinal Chemistry 2010; 17 (18) . https://dx.doi.org/10.2174/092986710791163957
DOI https://dx.doi.org/10.2174/092986710791163957 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
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