title: Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9.
abstract: Oligonucleotides containing an immune-stimulatory motif and an immune-regulatory motif act as antagonists of Toll-like receptor (TLR)7 and TLR9. In the present study, we designed and synthesized oligonucleotide-based antagonists of TLR7, 8 and 9 containing a 7-deaza-dG or arabino-G modification in the immune-stimulatory motif and 2'-O-methylribonucleotides as the immune-regulatory motif. We evaluated the biological properties of these novel synthetic oligoribonucleotides as antagonists of TLRs 7, 8 and 9 in murine and human cell-based assays and in vivo in mice and non-human primates. In HEK293, mouse and human cell-based assays, the antagonist compounds inhibited signaling pathways and production of a broad range of cytokines, including tumour necrosis factor alpha (TNF-α), interleukin (IL)-12, IL-6, interferon (IFN)-α, IL-1β and interferon gamma-induced protein (IP)-10, mediated by TLR7, 8 and 9. In vivo in mice, the antagonist compounds inhibited TLR7- and TLR9-mediated cytokine induction in a dose- and time-dependent fashion. Peripheral blood mononuclear cells (PBMCs) obtained from antagonist compound-treated monkeys secreted lower levels of TLR7-, 8- and 9-mediated cytokines than did PBMCs taken before antagonist administration. The antagonist compounds described herein provide novel agents for the potential treatment of autoimmune and inflammatory diseases.
authors: Idera Pharmaceuticals, Inc., 167 Sidney Street, Cambridge, MA 02139, USA.
authors: Ekambar R
authors: ER
authors: Kandimalla
authors: Lakshmi
authors: L
authors: Bhagat
authors: Daqing
authors: D
authors: Wang
authors: Dong
authors: D
authors: Yu
authors: Tim
authors: T
authors: Sullivan
authors: Nicola
authors: N
authors: La Monica
authors: Sudhir
authors: S
authors: Agrawal
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009843:Oligoribonucleotides / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D009843:Oligoribonucleotides; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases
references: J Immunol. 2005 Nov 1;175(9):6226-34
references: 16237121
references: Intern Med J. 2012 Sep;42(9):968-78
references: 22827853
references: Bioconjug Chem. 2002 Sep-Oct;13(5):966-74
references: 12236778
references: Nat Rev Nephrol. 2011 Oct 18;7(12):718-29
references: 22009248
references: Nucleic Acids Res. 2003 May 1;31(9):2393-400
references: 12711684
references: Arthritis Rheum. 2009 Sep;60(9):2767-71
references: 19714644
references: Antisense Nucleic Acid Drug Dev. 2001 Aug;11(4):247-56
references: 11572601
references: Lupus. 1996 Jun;5 Suppl 1:S4-10
references: 8803903
references: Clin Immunol. 2012 Jun;143(3):210-21
references: 22525889
references: J Med Chem. 2009 Nov 12;52(21):6871-9
references: 19824640
references: J Autoimmun. 2010 Jun;34(4):339-48
references: 19944565
references: J Med Chem. 2007 Dec 13;50(25):6411-8
references: 17988082
references: Mediators Inflamm. 2010;2010:986596
references: 20490286
references: Drugs. 2012 Oct 1;72(14):1867-80
references: 22938141
references: Curr Rheumatol Rep. 2005 Dec;7(6):463-8
references: 16303107
references: J Clin Invest. 2010 Oct;120(10):3651-62
references: 20811154
references: Nature. 2007 Oct 4;449(7162):564-9
references: 17873860
references: J Immunol. 2003 Aug 1;171(3):1393-400
references: 12874230
references: Bioorg Med Chem Lett. 1999 Dec 20;9(24):3453-8
references: 10617090
references: Curr Cancer Drug Targets. 2001 Nov;1(3):197-209
references: 12188879
references: Antisense Nucleic Acid Drug Dev. 1997 Jun;7(3):245-9
references: 9212919
references: J Immunol. 2005 May 1;174(9):5193-200
references: 15843514
references: Arthritis Rheum. 2005 Feb;52(2):651-8
references: 15692999
references: Arthritis Res Ther. 2012 Jun 12;14(3):R142
references: 22691272
references: J Am Soc Nephrol. 2005 Nov;16(11):3273-80
references: 16176997
references: J Immunol. 2011 Apr 15;186(8):4794-804
references: 21398612
references: Nat Immunol. 2010 May;11(5):373-84
references: 20404851
references: Int Immunol. 2011 Mar;23(3):203-14
references: 21393636
references: J Clin Invest. 2006 Feb;116(2):456-64
references: 16440059
references: Clin Rev Allergy Immunol. 2012 Apr;42(2):145-53
references: 21221847
references: J Exp Med. 2005 Oct 17;202(8):1131-9
references: 16230478
references: Bioconjug Chem. 2010 Jan;21(1):39-45
references: 20020767
references: J Endotoxin Res. 2006;12(6):379-84
references: 17254393
references: J Immunol. 2010 Feb 15;184(4):1840-8
references: 20089701
references: Bioorg Med Chem Lett. 2000 Dec 4;10(23):2585-8
references: 11128629
references: Arthritis Res Ther. 2009;11(3):R79
references: 19476613
references: Immunity. 2006 Sep;25(3):417-28
references: 16973389
references: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2620-5
references: 9122245
references: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13750-5
references: 17698957
references: Nat Biotechnol. 2012 Jan 09;30(1):69-77
references: 22231104
references: Immunol Res. 2012 Sep;53(1-3):58-77
references: 22434514
references: Bioorg Med Chem. 2001 Nov;9(11):2803-8
references: 11597460
references: Nucleic Acids Res. 2002 Oct 15;30(20):4460-9
references: 12384593
references: J Interferon Cytokine Res. 2011 Dec;31(12):887-92
references: 21923413
references: Arthritis Rheum. 2004 May;50(5):1686-9
references: 15146440
references: Clin Immunol. 2000 Sep;96(3):198-204
references: 10964537
references: Eur J Immunol. 2007 Dec;37(12):3582-6
references: 18034431
references: Nature. 2010 Jun 17;465(7300):937-41
references: 20559388
references: J Immunol. 2004 Oct 15;173(8):5002-7
references: 15470043
references: Bioorg Med Chem Lett. 2000 May 15;10(10):1051-4
references: 10843214
references: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12631-6
references: 9770537
references: J Med Chem. 2009 Jan 22;52(2):551-8
references: 19102653
references: Arthritis Res Ther. 2012 Jun 27;14(3):R155
references: 22734582
references: J Med Chem. 2009 Aug 27;52(16):5108-14
references: 19650625