Immuno-regulatory oligonucleotide compounds (IRO) to modulate the Toll-like receptor-based immune response

摘要

A TLR antagonist compound having the structure ** Formula ** in which: CG is an oligonucleotide moiety and C is cytosine or a pyrimidine nucleotide derivative, in which the pyrimidine nucleotide derivative is selected from the group that it consists of 5-hydroxycytosine, 5-hydroxymethylcytosine, N4-alkylcytosine, N4-ethylcytosine, araC, 5-OH-dC, N3-Me-dC, and 4-thiouracil; G is guanosine or a purine nucleotide derivative, wherein the purine nucleotide derivative is selected from the group consisting of 7-deaza-G, 7- deaza-dG, ara-G, 6-thio-G, Inosine , Iso-G, loxoribine, TOG (7-thio-8-oxo) -G, 8-bromo-G, 8-hydroxy-G, 5-aminoformicin B, Oxoformicin, 7-methyl-G, 9-p-chlorophenyl -8-aza-G, 9-phenyl-G, 9-hexyl-guanine, 7-deaza-9-benzyl-G, 6-Chloro-7- deazaguanine, 6-methoxy-7-deazaguanine, 8-Aza-7 -deaza-G (PPG), 2- (Dimethylamino) guanosine, 7-Methyl-6- thioguanosine, 8-Benzyloxyguanosine, 9-Deazaguanosine, 1- (BD-ribofuranosyl) -2-oxo-7-deaza-8-methyl -purine and 1- (2'- deoxy-β-D-ribofuranosyl) -2-oxo-7-deaza-8-methyl-purine; N1-N3, at each occurrence, is independently a nucleotide, a nucleotide derivative that is a purine or pyrimidine nucleotide that has a base that is not guanine, cytosine, adenine, thymine or uracil and / or a sugar that is not ribose or 2'-deoxyribose and may be present in the nucleus of an oligonucleotide or non-nucleotide junction that can bind or can bind to oligonucleotides by a different linkage to one containing phosphorus; Nm, at each occurrence, is independently a nucleotide, a nucleotide derivative that is a purine or pyrimidine nucleotide that has a base that is not guanine, cytosine, adenine, thymine or uracil and / or a sugar that is not ribose or 2 ' deoxyribose and can be present in the nucleus of an oligonucleotide, or non-nucleotide junction that can bind or can bind to oligonucleotides by a different linkage to one containing phosphorus; provided that at least one of N1 to N3 is a nucleotide derivative or non-nucleotide junction; and also provided that the compound contains less than 4 consecutive guanosine nucleotides; in which the rest of the oligonucleotide would be immune stimulator if it were not for the nucleotide derivative or non-nucleotide junction; in which m is a number from 0 to about 30; and wherein the TLR antagonist compound is not an antisense oligonucleotide; for use in the therapeutic treatment or prevention of a disease mediated by a TLR in a vertebrate, in which the disease is cancer, an autoimmune disorder, inflammation of the airways, inflammatory disorders, infectious disease, skin disorders, allergy, asthma or a disease caused by a pathogen.