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Issue 6, 2013
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Design of synthetic oligoribonucleotide-based agonists of Toll-like receptor 3 and their immune response profiles in vitro and in vivo

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Abstract

Double-stranded RNA of viral origin and enzymatically synthesized poly I:C act as agonists of TLR3 and induce immune responses. We have designed and synthesized double-stranded synthetic oligoribonucleotides (dsORNs) which act as agonists of TLR3. Each strand of dsORN contains two distinct segments, namely an alignment segment composed of a heteronucleotide sequence and an oligo inosine (I) or an oligo cytidine (C) segment. We report here the results of studies of dsORNs containing varying lengths and compositions of alignment and oligo I/oligo C segments. dsORNs of 50-mer length with a 15-mer alignment segment and a 35-mer oligo I/oligo C segment form stable duplexes under physiological conditions and induce TLR3-mediated immune responses. dsORNs activated the IRF3 signaling pathway in J774 cells, induced production of cytokines, including IFN-β, IFN-α, IP-10, IL-12 and IL-6, in murine and human cell-based assays and also induced multiple cytokines following systemic administration in mice and non-human primates.

Graphical abstract: Design of synthetic oligoribonucleotide-based agonists of Toll-like receptor 3 and their immune response profiles in vitro and in vivo

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Publication details

The article was received on 04 Oct 2012, accepted on 10 Dec 2012 and first published on 11 Dec 2012


Article type: Paper
DOI: 10.1039/C2OB26946E
Org. Biomol. Chem., 2013,11, 1049-1058

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    Design of synthetic oligoribonucleotide-based agonists of Toll-like receptor 3 and their immune response profiles in vitro and in vivo

    T. Lan, D. Wang, L. Bhagat, V. J. Philbin, D. Yu, J. X. Tang, M. R. Putta, T. Sullivan, N. La Monica, E. R. Kandimalla and S. Agrawal, Org. Biomol. Chem., 2013, 11, 1049
    DOI: 10.1039/C2OB26946E

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