Recognition of nucleic acid ligands by toll-like receptors 7/8: Importance of chemical modification

Current Medicinal Chemistry

Volumn 19, Issue 9, 2012, Pages 1365-1377

  Yu, Hui ^a,b   Wang, Zhanli ^b   Sun, Gang ^b   Yu, Yongchun ^a  

^a TONGJI UNIVERSITY   (China)

^b BAOTOU MEDICAL COLLEGE   (China)

Author keywords

Autoimmune disease; chemical modification; infectious disease; nucleoside analogues; oligodeoxynucleotides; oligoribonucleotide; single stranded RNA; small interfering RNA; structure activity relationships; toll like receptors

Indexed keywords

CPG OLIGODEOXYNUCLEOTIDE; IMIDAZOLE; IMIQUIMOD; NUCLEIC ACID; NUCLEOSIDE ANALOG; RESIQUIMOD; SINGLE STRANDED RNA; SMALL INTERFERING RNA; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TRIAZOLE;

CHEMICAL MODIFICATION; CHEMICAL STRUCTURE; DRUG STRUCTURE; HUMAN; IMMUNE RESPONSE; NEOPLASM; NONHUMAN; PROTEIN STRUCTURE; REVIEW; SEQUENCE ANALYSIS; STRUCTURE ACTIVITY RELATION; VIRUS INFECTION;

ANIMALS; AUTOIMMUNE DISEASES; HUMANS; IMMUNOLOGIC FACTORS; MODELS, MOLECULAR; NUCLEIC ACIDS; TOLL-LIKE RECEPTOR 7; TOLL-LIKE RECEPTOR 8;

EID: 84863229903     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/092986712799462603     Document Type: Review

References (150)

1. Janeway, C.; Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol., 2002, 20, 197-216. (Pubitemid 34293424)
2. Kawai, T.; Akira, S. TLR signaling. Cell Death Differ., 2006, 13, 816-825.
3. Takeda, K.; Kaisho, T.; Akira, S. Toll-like receptors. Annu. Rev. Immunol., 2003, 21, 335-376. (Pubitemid 37174535)
4. Aliprantis, A.O.; Yang, R.B.; Mark, M.R.; Suggett, S.; Devaux, B.; Radolf, J.D.; Klimpel, G.R.; Godowski, P.; Zychlinsky, A. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science, 1999, 285, 736-739.
5. Schwandner, R.; Dziarski, R.; Wesche, H.; Rothe, M.; Kirschning, C. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J. Biol. Chem., 1999, 274, 17406-17409.
6. Alexopoulou, L.; Holt, A.C.; Medzhitov, R.; Flavell, R.A. Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature, 2001, 413, 732-738. (Pubitemid 33009951)
7. Poltorak, A.; He, X.; Smirnova, I.; Liu, M.Y.; Van Huffel, C.; Du, X.; Birdwell, D.; Alejos, E.; Silva, M.; Galanos, C.; Freudenberg, M.; Ricciardi-Castagnoli, P.; Layton, B.; Beutler, B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science, 1998, 282, 2085-2088. (Pubitemid 29001265)
8. Takeuchi, O.; Hoshino, K.; Kawai, T.; Sanjo, H.; Takada, H.; Ogawa, T.; Takeda, K.; Akira, S. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity, 1999, 11, 443-451. (Pubitemid 29504199)
9. Latz, E.; Visintin, A.; Lien, E.; Fitzgerald, K.A.; Monks, B.G.; Kurt-Jones, E.A.; Golenbock, D.T.; Espevik, T. Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J. Biol. Chem., 2002, 277, 47834-47843. (Pubitemid 36159310)
10. Hayashi, F.; Smith, K.D.; Ozinsky, A.; Hawn, T.R.; Yi, E.C.; Goodlett, D.R.; Eng, J.K.; Akira, S.; Underhill, D.M.; Aderem, A. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature, 2001, 410, 1099-1103. (Pubitemid 32391041)
11. Heil, F.; Hemmi, H.; Hochrein, H.; Ampenberger, F.; Kirschning, C.; Akira, S.; Lipford, G.; Wagner, H.; Bauer, S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science, 2004, 303, 1526-1529. (Pubitemid 38314424)
12. Lund, J.M.; Alexopoulou, L.; Sato, A.; Karow, M.; Adams, N.C.; Gale, N.W.; Iwasaki, A.; Flavell, R.A. Recognition of single-stranded RNA viruses by toll-like receptor 7. Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5598-5603. (Pubitemid 38481202)
13. Hemmi, H.; Takeuchi, O.; Kawai, T.; Kaisho, T.; Sato, S.; Sanjo, H.; Matsumoto, M.; Hoshino, K.; Wagner, H.; Takeda, K.; Akira, S. A toll-like receptor recognizes bacterial DNA. Nature, 2000, 408, 740-745. (Pubitemid 32015992)
14. Brodsky. I.; Medzhitov, R. Two modes of ligand recognition by TLRs. Cell, 2007, 130, 979-981. (Pubitemid 47410282)
15. Jin, M.S.; Kim, S.E.; Heo, J.Y.; Lee, M.E.; Kim, H.M.; Paik, S.G.; Lee, H.; Lee, J.O. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell, 2007, 130, 1071-1082
16. Choe, J.; Kelker, M.S.; Wilson, I.A. Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science, 2005, 309, 581-585. (Pubitemid 41033635)
17. Bell, J.K.; Botos, I.; Hall, P.R.; Askins, J.; Shiloach, J.; Segal, D.M.; Davies, D.R. The molecular structure of the toll-like receptor 3 ligand-binding domain. Proc. Natl. Acad. Sci. U. S. A., 2005, 102, 10976-10980. (Pubitemid 41105978)
18. Liu, L.; Botos, I.; Wang, Y.; Leonard, J.N.; Shiloach, J.; Segal, D.M.; Davies, D.R. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science, 2008, 320, 379-381. (Pubitemid 351555661)
19. Kim, H.M.; Park, B.S.; Kim, J.I.; Kim, S.E.; Lee, J.; Oh, S.C.; Enkhbayar, P.; Matsushima, N.; Lee, H.; Yoo, O.J.; Lee, J.O. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell, 2007, 130, 906-917.
20. Kubarenko, A.; Frank, M.; Weber, A.N. Structure-function relationships of toll-like receptor domains through homology modelling and molecular dynamics. Biochem. Soc. Trans., 2007, 35, 1515-1518.
21. Wei, T.; Gong, J.; Jamitzky, F.; Heckl, W.M.; Stark, R.W.; Rössle, S.C. Homology modeling of human toll-like receptors TLR7, 8, and 9 ligand-binding domains. Protein Sci., 2009, 18, 1684-1691.
22. Kubarenko, A.V.; Ranjan, S.; Colak, E.; George, J.; Frank, M.; Weber, A.N. Comprehensive modeling and functional analysis of toll-like receptor ligand-recognition domains. Protein Sci., 2010, 19, 558-569.
23. Wei, T.; Gong, J.; Rössle, S.C.; Jamitzky, F.; Heckl, W.M.; Stark, R.W. A leucine-rich repeat assembly approach for homology modeling of the human TLR5-10 and mouse TLR11-13 ectodomains. J. Mol. Model., 2011, 17, 27-36.
24. Offord. V.; Coffey, T.J.; Werling, D. LRRfinder: a web application for the identification of leucine-rich repeats and an integrative toll-like receptor database. Dev. Comp. Immunol., 2010, 34, 1035-1041.
25. Diebold. S.S. Recognition of viral single-stranded RNA by toll-like receptors. Adv. Drug Deliv. Rev., 2008, 60, 813-823.
26. Thompson, A.J.; Locarnini, S.A. Toll-like receptors, RIG-I-like RNA helicases and the antiviral innate immune response. Immunol. Cell Biol., 2007, 85, 435-445. (Pubitemid 47367510)
27. Smits, E.L.; Ponsaerts, P.; Berneman, Z.N.; Van Tendeloo, V.F. The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. Oncologist, 2008, 13, 859-875.
28. Fitzgerald-Bocarsly, P.; Dai, J.; Singh, S. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history. Cytokine Growth Factor Rev., 2008, 19, 3-19.
29. O'Neill, L.A. Primer: toll-like receptor signaling pathways - what do rheumatologists need to know? Nat. Clin. Pract. Rheumatol., 2008, 4, 319-327. (Pubitemid 351791443)
30. Kawai, T.; Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Ann. N. Y. Acad. Sci., 2008, 1143, 1-20.
31. Guiducci, C.; Coffman, R.L.; Barrat, F.J. Signalling pathways leading to IFN-alpha production in human plasmacytoid dendritic cell and the possible use of agonists or antagonists of TLR7 and TLR9 in clinical indications. J. Intern. Med., 2009, 265, 43-57.
32. Wolska, A.; Lech-Marańda, E.; Robak, T. Toll-like receptors and their role in carcinogenesis and anti-tumor treatment. Cell Mol. Biol. Lett., 2009, 14, 248-272.
33. Khoo, J.J.; Forster, S.; Mansell, A. Toll-like receptors as interferon-regulated genes and their role in disease. J. Interferon Cytokine Res., 2011, 31, 13-25.
34. Schön, M.P.; Schön, M. TLR7 and TLR8 as targets in cancer therapy. Oncogene, 2008, 27, 190-199.
35. Fletcher, S.; Steffy, K.; Averett, D. Masked oral prodrugs of toll-like receptor 7 agonists: a new approach for the treatment of infectious disease. Curr. Opin. Investig. Drugs, 2006, 7, 702-708.
36. Meyers, A.J.; Shah, R.R.; Gottlieb, P.A.; Zipris, D. Altered toll-like receptor signaling pathways in human type 1 diabetes. J. Mol. Med. (Berl), 2010, 88, 1221-1231.
37. Averett, D.R.; Fletcher, S.P.; Li, W.; Webber, S.E.; Appleman, J.R. The pharmacology of endosomal TLR agonists in viral disease. Biochem. Soc. Trans., 2007, 35, 1468-1472.
38. Miller, R.L.; Meng, T.C.; Tomai, M.A. The antiviral activity of toll-like receptor 7 and 7/8 agonists. Drug News Perspect., 2008, 21, 69-87. (Pubitemid 351628232)
39. Gutierrez-Roelens, I.; Lauwerys, B.R. Genetic susceptibility to autoimmune disorders: clues from gene association and gene expression studies. Curr. Mol. Med., 2008, 8, 551-561.
40. Trivedi, S.; Greidinger, E.L. Endosomal toll-like receptors in autoimmunity: mechanisms for clinical diversity. Therapy, 2009, 6, 433-442.
41. Guiducci, C.; Gong, M.; Xu, Z.; Gill, M.; Chaussabel, D.; Meeker, T.; Chan, J.H.; Wright, T.; Punaro, M.; Bolland, S.; Soumelis, V.; Banchereau, J.; Coffman, R.L.; Pascual, V.; Barrat, F.J. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature, 2010, 465, 937-941.
42. Richez, C.; Blanco, P.; Rifkin, I.; Moreau, J.F.; Schaeverbeke, T. Role for toll-like receptors in autoimmune disease: the example of systemic lupus erythematosus. Joint Bone Spine, 2011, 78, 124-130.
43. Green, N.M.; Marshak-Rothstein, A. Toll-like receptor driven B cell activation in the induction of systemic autoimmunity. Semin. Immunol., 2011, 23, 106-112.
44. Barrat, F.J.; Coffman, R.L. Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol. Rev., 2008, 223, 271-283. (Pubitemid 351986175)
45. Diebold, S.S.; Kaisho, T.; Hemmi, H.; Akira, S.; Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science, 2004, 303, 1529-1531.
46. Krug, A. Nucleic acid recognition receptors in autoimmunity. Handb. Exp. Pharmacol., 2008, (183), 129-151.
47. Peng, G.; Guo, Z.; Kiniwa, Y.; Voo, K.S.; Peng, W.; Fu, T.; Wang, D.Y.; Li, Y.; Wang, H.Y.; Wang, R.F. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science, 2005, 309, 1380-1384.
48. Villanueva, A.I.; Kulkarni, R.R.; Sharif, S. Synthetic double-stranded RNA oligonucleotides are immunostimulatory for chicken spleen cells. Dev. Comp. Immunol., 2011, 35, 28-34.
49. Buza, J.; Benjamin, P.; Zhu, J.; Wilson, H.L.; Lipford, G.; Krieg, A.M.; Babiuk, L.A.; Mutwiri, G.K. CD14+ cells are required for IL-12 response in bovine blood mononuclear cells activated with Toll-like receptor (TLR) 7 and TLR8 ligands. Vet. Immunol. Immunopathol., 2008, 126, 273-282.
50. Ablasser, A.; Poeck, H.; Anz, D.; Berger, M.; Schlee, M.; Kim, S.; Bourquin, C.; Goutagny, N.; Jiang, Z.; Fitzgerald, K.A.; Rothenfusser, S.; Endres, S.; Hartmann, G.; Hornung, V. Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes. J. Immunol., 2009, 182, 6824-6833.
51. Heil, F.; Ahmad-Nejad, P.; Hemmi, H.; Hochrein, H.; Ampenberger, F.; Gellert, T.; Dietrich, H.; Lipford, G.; Takeda, K.; Akira, S.; Wagner, H.; Bauer, S. The toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol., 2003, 33, 2987-2997. (Pubitemid 37428331)
52. Hemmi, H.; Kaisho, T.; Takeuchi, O.; Sato, S.; Sanjo, H.; Hoshino, K.; Horiuchi, T.; Tomizawa, H.; Takeda, K.; Akira, S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signalling pathway. Nat. Immunol., 2002, 3, 196-200. (Pubitemid 34141451)
53. Jurk, M.; Heil, F.; Vollmer, J.; Schetter, C.; Krieg, A.M.; Wagner, H.; Lipford, G.; Bauer, S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol., 2002, 3, 499. (Pubitemid 34669818)
54. Lee, J.; Chuang, T.H.; Redecke, V.; She, L.; Pitha, P.M.; Carson, D.A.; Raz, E.; Cottam, H.B. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of toll-like receptor 7. Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 6646-6651. (Pubitemid 36666635)
55. Sioud, M. Deciphering the code of innate immunity recognition of siRNAs. Methods Mol. Biol., 2009, 487, 41-59.
56. Sioud, M. Does the understanding of immune activation by RNA predict the design of safe siRNAs? Front. Biosci., 2008, 13, 4379-4392. (Pubitemid 351599690)
57. Diebold, S.S.; Massacrier, C.; Akira, S.; Paturel, C.; Morel, Y.; Reis e Sousa, C. Nucleic acid agonists for toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur. J. Immunol., 2006, 36: 3256-3267.
58. Hornung, V.; Guenthner-Biller, M.; Bourquin, C.; Ablasser, A.; Schlee, M.; Uematsu, S.; Noronha, A.; Manoharan, M.; Akira, S.; de Fougerolles, A.; Endres, S.; Hartmann, G. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med., 2005, 11, 263-270. (Pubitemid 40460553)
59. Kariko, K.; Buckstein, M.; Ni, H.; Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity, 2005, 23, 165-175. (Pubitemid 41169286)
60. Robbins, M.; Judge, A.; Liang, L.; McClintock, K.; Yaworski, E.; MacLachlan, I. 2′-O-methyl-modified RNAs act as TLR7 antagonists. Mol. Ther., 2007; 15, 1663-1669. (Pubitemid 47289010)
61. Maden, B.E. The numerous modified nucleotides in eukaryotic ribosomal RNA. Prog. Nucleic. Acid Res. Mol. Biol., 1990, 39, 241-303.
62. Ishii, K.J.; Akira, S. TLR ignores methylated RNA? Immunity, 2005, 23, 111-113. (Pubitemid 41169280)
63. Sioud, M. Innate sensing of self and non-self RNAs by Toll-like receptors. Trends Mol. Med., 2006, 12, 167-176.
64. Tluk, S.; Jurk, M.; Forsbach, A.; Weeratna, R.; Samulowitz, U.; Krieg, A.M.; Bauer, S.; Vollmer, J. Sequences derived from self-RNA containing certain natural modifications act as suppressors of RNA-mediated inflammatory immune responses. Int. Immunol., 2009, 21, 607-619.
65. Barchet, W.; Krug, A.; Cella, M.; Newby, C.; Fischer, J.A.; Dzionek, A.; Pekosz, A.; Colonna, M. Dendritic cells respond to influenza virus through TLR7- and PKR-independent pathways. Eur. J. Immunol., 2005, 35, 236-242. (Pubitemid 40123870)
66. Zhang, Y.; Guo, Y.; Lv, K.; Wang, K.; Sun, S. Molecular cloning and functional characterization of porcine toll-like receptor 7 involved in recognition of single-stranded RNA virus/ssRNA. Mol. Immunol., 2008, 45, 1184-1190. (Pubitemid 350016327)
67. Bourquin, C.; Schmidt, L.; Hornung, V.; Wurzenberger, C.; Anz, D.; Sandholzer, N.; Schreiber, S.; Voelkl, A.; Hartmann, G.; Endres, S. Immunostimulatory RNA oligonucleotides trigger an antigen-specific cytotoxic T cell and IgG2a response. Blood, 2006, 109, 2953-2960. (Pubitemid 46482093)
68. Lan, T.; Kandimalla, E.R.; Yu, D.; Bhagat, L.; Li, Y.; Wang, D.; Zhu, F.; Tang, J. X.; Putta, M.R.; Cong, Y.; Trombino, A.F.; Sullivan, T.; Agrawal, S. Stabilized immune modulatory RNA compounds as agonists of toll-like receptors 7 and 8. Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 13750-13755. (Pubitemid 350003392)
69. Lan, T.; Bhagat, L.; Wang, D.; Dai, M.; Kandimalla, E.R.; Agrawal, S. Synthetic oligoribonucleotides containing arabinonucleotides act as agonists of TLR7 and 8. Bioorg. Med. Chem. Lett., 2009, 19, 2044-2047.
70. Lan, T.; Putta, M.R.; Wang, D.; Dai, M.; Yu, D.; Kandimalla, E.R.; Agrawal, S. Synthetic oligoribonucleotides-containing secondary structures act as agonists of toll-like receptors 7 and 8. Biochem. Biophys. Res. Commun., 2009, 386, 443-448.
71. Lan, T.; Dai, M.; Wang, D.; Zhu, F.G.; Kandimalla, E.R.; Agrawal, S. Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure-activity relationship studies. J. Med. Chem., 2009, 52, 6871-6879.
72. Kandimalla, E.R.; Struthers, M.; Bett, A.J.; Wisniewski, T.; Dubey, S.A.; Jiang, W.; Precopio, M.; Sun, Z.; Wang, H.; Lan, T.; Agrawal, S.; Casimiro, D.R. Synthesis and immunological activities of novel Toll-like receptor 7 and 8 agonists. Cell. Immunol., 2011, 270, 126-134.
73. Anz, D.; Koelzer, V.H.; Moder, S.; Thaler, R.; Schwerd, T.; Lahl, K.; Sparwasser, T.; Besch, R.; Poeck, H.; Hornung, V.; Hartmann, G.; Rothenfusser, S.; Bourquin, C.; Endres, S. Immunostimulatory RNA blocks suppression by regulatory T cells. J. Immunol., 2010, 184, 939-946.
74. Sioud. M. Development of TLR7/8 small RNA antagonists. Methods Mol. Biol., 2010, 629, 387-394.
75. Forsbach, A.; Nemorin, J.G.; Montino, C.; Müller, C.; Samulowitz, U.; Vicari, A.P.; Jurk, M.; Mutwiri, G.K.; Krieg, A.M.; Lipford, G.B.; Vollmer, J. Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses. J. Immunol., 2008, 180, 3729-3738.
76. Gantier, M.P., Tong, S., Behlke, M.A., Xu, D., Phipps, S., Foster, P.S., Williams, B.R. TLR7 is involved in sequence-specific sensing of single-stranded RNAs in human macrophages. J. Immunol., 2008, 180, 2117-2124.
77. Gorden, K.B.; Gorski, K.S.; Gibson, S.J.; Kedl, R.M.; Kieper, W.C.; Qiu, X.; Tomai, M.A.; Alkan, S.S.; Vasilakos, J.P. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J. Immunol., 2005, 174, 1259-1268.
78. Karikó, K.; Bhuyan, P.; Capodici, J.; Weissman, D. Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J. Immunol., 2004, 172, 6545-6549. (Pubitemid 38669088)
79. Sioud, M. Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. J. Mol. Biol., 2005, 348, 1079-1090. (Pubitemid 40602367)
80. Judge, A.D.; Sood, V.; Shaw, J.R.; Fang, D.; McClintock, K.; MacLachlan, I. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat. Biotechnol., 2005, 23, 457-462. (Pubitemid 41724921)
81. Sioud, M. Single-stranded small interfering RNA are more immunostimulatory than their double-stranded counterparts: a central role for 20-hydroxyl uridines in immune responses. Eur. J. Immunol., 2006, 36, 1222-1230.
82. Hornung, V.; Guenthner-Biller, M.; Bourquin, C.; Ablasser, A.; Schlee, M.; Uematsu, S.; Noronha, A.; Manoharan, M.; Akira, S.; de Fougerolles, A.; Endres, S.; Hartmann, G. Sequence-specific potent induction of IFN-a by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med., 2005, 11, 263-270. (Pubitemid 40460553)
83. Zamanian-Daryoush, M.; Marques, J.T.; Gantier, M.P.; Behlke, M.A.; John, M.; Rayman, P.; Finke, J.; Williams, B.R. Determinants of cytokine induction by small interfering RNA in human peripheral blood mononuclear cells. J. Interferon Cytokine Res., 2008, 28, 221-233. (Pubitemid 351591447)
84. Gantier, M.P.; Williams, B.R. The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev., 2007, 18, 363-371. (Pubitemid 47302837)
85. Schlee, M.; Hornung, V.; Hartmann, G. siRNA and isRNA: two edges of one sword. Mol. Ther., 2006, 14, 463-470. (Pubitemid 44296098)
86. Goodchild, A.; Nopper, N.; King, A.; Doan, T.; Tanudji, M.; Arndt, G.M.; Poidinger, M.; Rivory, L.P.; Passioura, T. Sequence determinants of innate immune activation by short interfering RNAs. BMC. Immunol., 2009, 10, 40.
87. Amarzguioui, M.; Lundberg, P.; Cantin, E.; Hagstrom, J.; Behlke, M.A.; Rossi, J.J. Rational design and in vitro and in vivo delivery of Dicer substrate siRNA. Nat. Protoc., 2006, 1, 508-517.
88. Rose, S.D., Kim, D.H., Amarzguioui, M., Heidel, J.D., Collingwood, M.A., Davis, M.E., Rossi, J.J., Behlke, M.A. Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic. Acids Res., 2005, 33, 4140-4156. (Pubitemid 41487274)
89. Gantier, M.P.; Tong, S.; Behlke, M.A.; Irving, A.T.; Lappas, M.; Nilsson, U.W.; Latz, E.; McMillan, N.A.; Williams, B.R. Rational design of immunostimulatory siRNAs. Mol. Ther., 2010, 18, 785-795.
90. Ui-Tei, K.; Naito, Y.; Zenno, S.; Nishi, K.; Yamato, K.; Takahashi, F.; Juni, A.; Saigo, K. Functional dissection of siRNA sequence by systematic DNA substitution: modified siRNA with a DNA seed arm is a powerful tool for mammalian gene silencing with significantly reduced off-target effect. Nucl. Acids Res., 2008, 36, 2136-2151. (Pubitemid 351566989)
91. Chiu, Y.L.; Rana, T.M. siRNA function in RNAi: a chemical modification analysis. RNA, 2003, 9, 1034-1048. (Pubitemid 37093614)
92. Marques, J.T.; Devosse, T.; Wang, D.; Zamanian-Daryoush, M.; Serbinowski, P.; Hartmann, R.; Fujita, T.; Behlke, M.A.; Williams, B.R. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat. Biotechnol., 2006, 24, 559-565.
93. Fluiter, K.; Mook, O.R.; Baas, F. The therapeutic potential of LNA-modified siRNAs: reduction of off-target effects by chemical modification of the siRNA sequence. Methods Mol. Biol., 2009, 487, 189-203.
94. Shin, D.; Kim, S.I.; Park, M.; Kim, M. Immunostimulatory properties and antiviral activity of modified HBV-specific siRNAs. Biochem. Biophys. Res. Commun., 2007, 364, 436-442. (Pubitemid 350026488)
95. Odadzic, D.; Bramsen, J.B.; Smicius, R.; Bus, C.; Kjems, J.; Engels, J.W. Synthesis of 2′-O-modified adenosine building blocks and application for RNA interference. Bioorg. Med. Chem., 2008, 16, 518-529.
96. Gaynor, J.W.; Campbell, B.J.; Cosstick, R. RNA interference: a chemist's perspective. Chem. Soc. Rev., 2010, 39, 4169-4184.
97. Gaglione, M.; Messere, A. Recent progress in chemically modified siRNAs. Mini. Rev. Med. Chem., 2010, 10(7), 578-595.
98. Chernolovskaya, E.L.; Zenkova, M.A. Chemical modification of siRNA. Curr. Opin. Mol. Ther., 2010, 12,158-167.
99. Watts, J.K.; Deleavey, G.F.; Damha, M.J. Chemically modified siRNA: tools and applications. Drug Discov. Today, 2008, 13, 842-855.
100. Judge, A.D.; Bola, G.; Lee, A.C.; MacLachlan, I. Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol. Ther., 2006, 13, 494-505. (Pubitemid 43257617)
101. Cekaite, L.; Furset, G.; Hovig, E.; Sioud, M. Gene expression analysis in blood cells in response to unmodified and 2′-modified siRNAs reveals TLR-dependent and independent effects. J. Mol. Biol., 2007, 365, 90-108. (Pubitemid 44830036)
102. Sioud, M. RNA interference and innate immunity. Adv. Drug Deliv. Rev., 2007, 59, 153-163. (Pubitemid 46783844)
103. Robbins, M.; Judge, A.; Liang, L.; McClintock, K.; Yaworski, E.; MacLachlan, I. 2′-O-methyl-modified RNAs act as TLR7 antagonists. Mol. Ther., 2007, 15, 1663-1669. (Pubitemid 47289010)
104. Sioud, M.; Furset, G.; Cekaite, L. Suppression of immunostimulatory siRNA-driven innate immune activation by 2′-modified RNAs. Biochem. Biophys. Res. Commun., 2007, 361, 122-126. (Pubitemid 47102276)
105. Morrissey, D.V.; Lockridge, J.A.; Shaw, L.; Blanchard, K.; Jensen, K.; Breen, W.; Hartsough, K.; Machemer, L.; Radka, S.; Jadhav, V.; Vaish, N.; Zinnen, S.; Vargeese, C.; Bowman, K.; Shaffer, C.S.; Jeffs, L.B.; Judge, A.; MacLachlan, I.; Polisky, B. Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nat. Biotechnol., 2005, 23, 1002-1007. (Pubitemid 41114035)
106. Behlke, M.A. Chemical modification of siRNAs for in vivo use. Oligonucleotides, 2008, 18, 305-319. (Pubitemid 352791344)
107. Marques, J.T.; Williams, B.R. Activation of the mammalian immune system by siRNAs. Nat. Biotechnol., 2005, 23, 1399-1405. (Pubitemid 41679392)
108. Furset, G.; Sioud, M. Design of bifunctional siRNAs: combining immunostimulation and gene-silencing in one single siRNA molecule. Biochem. Biophys. Res. Commun., 2007, 352, 642-649. (Pubitemid 44880303)
109. Poeck, H.; Besch, R.; Maihoefer, C.; Renn, M.; Tormo, D.; Morskaya, S.S.; Kirschnek, S.; Gaffal, E.; Landsberg, J.; Hellmuth, J.; Schmidt, A.; Anz, D.; Bscheider, M.; Schwerd, T.; Berking, C.; Bourquin, C.; Kalinke, U.; Kremmer, E.; Kato, H.; Akira, S.; Meyers, R.; Häcker, G.; Neuenhahn, M.; Busch, D.; Ruland, J.; Rothenfusser, S.; Prinz, M.; Hornung, V.; Endres, S.; Tüting, T.; Hartmann, G. 5′-Triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat. Med., 2008, 14, 1256-1263.
110. Flatekval, G.F.; Sioud, M. Modulation of dendritic cell maturation and function with mono- and bifunctional small interfering RNAs targeting indoleamine 2,3-dioxygenase. Immunology, 2009, 128, e837-e848.
111. Ehsani, A.; Saetrom, P.; Zhang, J.; Alluin, J.; Li, H.; Snøve, O. Jr.; Aagaard, L.; Rossi, J.J. Rational design of micro-RNA-like bifunctional siRNAs targeting HIV and the HIV coreceptor CCR5. Mol. Ther., 2010, 18, 796-802.
112. Khairuddin, N.; Gantier, M.P.; Blake, S.J.; Wu, S.Y.; Behlke, M.A.; Williams, B.R.; McMillan, N.A. siRNA-induced immunostimulation through TLR7 promotes antitumoral activity against HPV-driven tumors in vivo. Immunol. Cell Biol., 2011, [Epub]
113. Jurk, M.; Chikh, G.; Schulte, B.; Kritzler, A.; Richardt-Pargmann, D.; Lampron, C.; Luu, R.; Krieg, A.M.; Vicari, A.P.; Vollmer, J. Immunostimulatory potential of silencing RNAs can be mediated by a non-uridine-rich toll-like receptor 7 motif. Nucleic. Acid Ther., 2011, 21, 201-214.
114. Sioud, M. Advances in RNA sensing by the immune system: separation of siRNA unwanted effects from RNA interference. Methods Mol. Biol., 2010, 629, 33-52.
115. Robbins, M.; Judge, A.; Ambegia, E.; Choi, C.; Yaworski, E.; Palmer, L.; McClintock, K.; MacLachlan, I. Misinterpreting the therapeutic effects of small interfering RNA caused by immune stimulation. Hum. Gene Ther., 2008, 19, 991-999.
116. Nguyen, D.N.; Chen, S.C.; Lu, J.; Goldberg, M.; Kim, P.; Sprague, A.; Novobrantseva, T.; Sherman, J.; Shulga-Morskaya, S.; de Fougerolles, A.; Chen, J.; Langer, R.; Anderson, D.G. Drug delivery-mediated control of RNA immunostimulation. Mol. Ther., 2009, 17, 1555-1562.
117. Gorden, K.K.; Qiu, X.X.; Binsfeld, C.C.; Vasilakos, J.P.; Alkan, S.S. Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J. Immunol., 2006, 177, 6584-6587. (Pubitemid 44715019)
118. Sun, R.; Sun, L.; Bao, M.; Zhang, Y.; Wang, L.; Wu, X.; Hu, D.; Liu, Y.; Yu, Y.; Wang, L. A human microsatellite DNA-mimicking oligodeoxynucleotide with CCT repeats negatively regulates TLR7/9-mediated innate immune responses via selected TLR pathways. Clin. Immunol., 2010, 134, 262-276.
119. Martinez, J.; Huang, X.; Yang, Y. Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA. Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 6442-6447.
120. Du, M.; Butchi, N.B.; Woods, T.; Peterson, K.E. Poly-thymidine oligonucleotides mediate activation of murine glial cells primarily through TLR7, not TLR8. PloS. One, 2011, 6, e22454.
121. Yu, D.; Kandimalla, E.R.; Zhao, Q.; Cong, Y.; Agrawal, S. Immunostimulatory properties of phosphorothioate CpG DNA containing both 3′-5′- and 2′-5′-internucleotide linkages. Nucleic Acids Res., 2003, 30, 1613-1619. (Pubitemid 34679736)
122. Agrawal, S.; Kandimalla, E.R. Antisense and/or immunostimulatory oligonucleotide therapeutics. Curr. Cancer Drug Targets, 2001, 1, 197-209. (Pubitemid 33772977)
123. Yu, D.; Kandimalla, E.R.; Zhao, Q.; Cong, Y.; Agrawal, S. Immunostimulatory activity of CpG oligonucleotides containing nonionic methylphosphonate linkages. Bioorg. Med. Chem., 2001, 9, 2803-2808.
124. Yu, D.; Kandimalla, E.R.; Zhao, Q.; Cong, Y.; Agrawal, S. Modulation of immunostimulatory activity of CpG oligonucleotides by site-specific deletion of nucleobases. Bioorg. Med. Chem. Lett., 2001, 11, 2263-2267. (Pubitemid 32781679)
125. Yu, D.; Kandimalla, E.R.; Zhao, Q.; Bhagat, L.; Cong, Y.; Agrawal, S. Requirement of nucleobase proximal to CpG dinucleotide for immunostimulatory activity of synthetic CpG DNA. Bioorg. Med. Chem., 2003, 11, 459-464. (Pubitemid 36051036)
126. Yu, D.; Kandimalla, E.R.; Cong, Y.; Tang, J.; Tang, J.Y.; Zhao, Q.; Agrawal, S. Design, synthesis, and immunostimulatory properties of CpG DNAs containing alkyl-linker substitutions: role of nucleosides in the flanking sequences. J. Med. Chem., 2002, 45, 4540-4548.
127. Zhao, Q.; Yu, D.; Agrawal, S. Site of chemical modifications in CpG containing phosphorothioate oligodeoxynucleotide modulates its immunostimulatory activity. Bioorg. Med. Chem. Lett., 1999, 9, 3453-3458.
128. Zhao, Q.; Yu, D.; Agrawal, S. Immunostimulatory activity of CpG containing phosphorothioate oligodeoxynucleotide is modulated by modification of a single deoxynucleoside. Bioorg. Med. Chem. Lett., 2000, 10, 1051-1054. (Pubitemid 30406464)
129. Wang, D.; Bhagat, L.; Yu, D.; Zhu, F.G.; Tang, J.X.; Kandimalla, E.R.; Agrawal, S. Oligodeoxyribonucleotide-based antagonists for Toll-like receptors 7 and 9. J Med Chem., 2009, 52, 551-558.
130. Yu, D.; Wang, D.; Zhu, F.G.; Bhagat, L.; Dai, M.; Kandimalla, E.R.; Agrawal, S. Modifications incorporated in CpG motifs of oligodeoxynucleotides lead to antagonist activity of toll-like receptors 7 and 9. J. Med. Chem., 2009, 52, 5108-5114.
131. Gorden, K.K.; Qiu, X.; Battiste, J.J.; Wightman, P.P.; Vasilakos, J.P.; Alkan, S.S. Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. J. Immunol., 2006, 177, 8164-8170. (Pubitemid 44846336)
132. Jurk, M.; Kritzler, A.; Schulte, B.; Tluk, S.; Schetter, C.; Krieg, A.M.; Vollmer, J. Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides. Eur. J. Immunol., 2006, 36, 1815-1826. (Pubitemid 44089048)
133. Graham, K.L.; Lee, L.Y.; Higgins, J.P.; Steinman, L.; Utz, P.J.; Ho, PP. Treatment with a Toll-like receptor inhibitory GpG oligonucleotide delays and attenuates lupus nephritis in NZB/W mice. Autoimmunity, 2010, 43, 140-155.
134. Lau, C.M.; Broughton, C.; Tabor, A.S.; Akira, S.; Flavell, R.A.; Mamula, M.J.; Christensen, S.R.; Shlomchik, M.J.; Viglianti, G.A.; Rifkin, I.R.; Marshak-Rothstein, A. RNAassociated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med., 2005, 202, 1171-1177. (Pubitemid 41586947)
135. Vollmer J, Tluk S, Schmitz C, Hamm S, Jurk M, Forsbach A, Akira S, Kelly KM, Reeves WH, Bauer S, Krieg AM. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves toll-like receptors 7 and 8. J. Exp. Med., 2005, 202, 1575-1585. (Pubitemid 41746603)
136. Yoshida, H.; Nishikawa, M.; Kiyota, T.; Uno, S.; Toyota, H.; Takahashi, R.; Narita, M.; Takakura, Y. 5′-Phosphate oligodeoxynucleotides enhance the phosphodiester-CpG DNA-induced inflammatory response in macrophages. Eur. J. Immunol., 2011, 41, 425-436.
137. Chan, M.; Hayashi, T.; Kuy, C.S.; Gray, C.S.; Wu, C.C.; Corr, M.; Wrasidlo, W.; Cottam, H.B.; Carson, D.A. Synthesis and immunological characterization of toll-like receptor 7 agonistic conjugates. Bioconjug. Chem., 2009, 20, 1194-1200.
138. Jones, P.; Pryde, C. 2-amido-6-amino-8-oxopurine derivatives as Toll-like receptor modulators for the treatment of cancer and viral infections, such as hepatitis C. W.O. Patent 2,006,117,670, November 09, 2006.
139. Jones, P.; Pryde, C.; Tran, T. 3-deazapurine derivatives as TLR7 modulators. W.O. Patent 200,709,301, August 23, 2007.
140. Chong, L.; Desai, M.; Gallagher, B.; Graupe, M.; Halcomb, R.; Yang, H.; Zhang, J. Modulators of toll-like receptor 7. W.O. Patent 200,805,555, January 10, 2008.
141. Cook, A.; Mcinally, T.; Thom, S.; Wada, H. 8-oxoadenine derivatives acting as modulators of TLR7. W.O. Patent 2,008,004,948, January 10, 2008.
142. Jin, G; Wu, C; Tawatao, R; Chan, M.; Carson, D.; Cottam, H. Synthesis and immunostimulatory activity of 8-substituted amino-9-benzyladenines as potent toll-like receptor 7 agonists. Bioorg. Med. Chem. Lett., 2006, 16, 4559-4563. (Pubitemid 44094075)
143. Shukla, N.M.; Malladi, S.S.; Mutz, C.A.; Balakrishna, R.; David, S.A. Structure-activity relationships in human toll-like receptor 7-active imidazoquinoline analogues. J. Med. Chem., 2010, 53, 4450-4465.
144. Kurimoto, A.; Hashimoto, K.; Nakamura, T.; Norimura, K.; Ogita, H.; Takaku, H.; Bonnert, R.; McInally, T.; Wada, H.; Isobe, Y. Synthesis and biological evaluation of 8-oxoadenine derivatives as toll-like receptor 7 agonists introducing the antedrug concept. J. Med. Chem., 2010, 53, 2964-2972.
145. Tran, T.D.; Pryde, D.C.; Jones, P.; Adam, F.M.; Benson, N.; Bish, G.; Calo, F.; Ciaramella, G.; Dixon, R.; Duckworth, J.; Fox, D.N.; Hay, D.A.; Hitchin, J.; Horscroft, N.; Howard, M.; Gardner, I.; Jones, H.M.; Laxton, C.; Parkinson, T.; Parsons, G.; Proctor, K.; Smith, M.C.; Smith, N.; Thomas, A. Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection. Bioorg. Med. Chem. Lett., 2011, 21, 2389-2393.
146. Gerster, J.F.; Lindstrom, K.J.; Miller, R.L.; Tomai, M.A.; Birmachu, W.; Bomersine, S.N.; Gibson, S.J.; Imbertson, L.M.; Jacobson, J.R.; Knafla, R.T.; Maye, P.V.; Nikolaides, N.; Oneyemi, F.Y.; Parkhurst, G.J.; Pecore, S.E.;
147. Weterings, J.J.; Khan, S.; van der Heden van Noort, G.J.; Melief, C.J.; Overkleeft, H.S.; van der Burg, S.H.; Ossendorp, F.; van der Marel, G.A.; Filippov, D.V. 2-Azidoalkoxy-7-hydro-8-oxoadenine derivatives as TLR7 agonists inducing dendritic cell maturation. Bioorg. Med. Chem. Lett., 2009, 19, 2249-2251.
148. Czarniecki, M. Small molecule modulators of toll-like receptors. J. Med. Chem., 2008, 51, 6621-6626.
149. Akira, S.; Hemmi, H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett., 2003, 85, 85-95. (Pubitemid 36071561)
150. Pope, B.L.; Chourmouzis, E.; Lee, S.; Goodman, M.G. Enhancement of immunostimulatory activity by dual substitution of C8-substituted guanine ribonucleosides: correlation with increased cytokine secretion. J. Immunother. Emphasis Tumor Immunol., 1995, 17, 98-108.