title: Immune-Stimulatory Dinucleotide at the 5'-End of Oligodeoxynucleotides Is Critical for TLR9-Mediated Immune Responses.
abstract: Oligodeoxynucleotides (ODNs) containing a CpG or certain synthetic dinucleotides, referred to as immune-stimulatory dinucleotides, induce Toll-like receptor 9 (TLR9)-mediated immune responses. Chemical modifications such as 2'-O-methylribonucleotides incorporated adjacent to the immune-stimulatory dinucleotide on the 5'-side abrogate TLR9-mediated immune responses. In this study, we evaluated the effect of the location of immune-stimulatory dinucleotides in ODNs on TLR9-mediated immune responses. We designed and synthesized ODNs with two immune-stimulatory dinucleotides, one placed toward the 5'-end region and the other toward the 3'-end region, incorporated 2'-O-methylribonucleotides selectively preceding the 5'- or 3'-immune-stimulatory dinucleotide or both, and studied TLR9-mediated immune responses of these compounds in cell-based assays and in vivo in mice. These studies showed that an immune-stimulatory dinucleotide located closer to the 5'-end is critical for and dictates TLR9-mediated immune responses. These studies provide insights for the use of ODNs when employed as TLR9 agonists and antagonists or antisense agents.
authors.affiliation: Idera Pharmaceuticals, Inc. , 167 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Putta
authors.affiliation: Idera Pharmaceuticals, Inc. , 167 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Bhagat
authors.affiliation: Idera Pharmaceuticals, Inc. , 167 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Daqing
authors.initials: D
authors.lastname: Wang
authors.affiliation: Idera Pharmaceuticals, Inc. , 167 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Fu-Gang
authors.initials: FG
authors.lastname: Zhu
authors.affiliation: Idera Pharmaceuticals, Inc. , 167 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Ekambar R
authors.initials: ER
authors.lastname: Kandimalla
authors.affiliation: Idera Pharmaceuticals, Inc. , 167 Sidney Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Agrawal
keywords: NF-κB; Toll-like receptor 9; immune stimulation; immune-stimulatory dinucleotide; oligodeoxynucleotides