Synthetic oligoribonucleotides containing secondary structures activate Toll-like receptor 8 and induce immune responses

MEDI 108

Tao Lan, tlan@iderapharma.com, Lakshmi Bhagat, Meiru Dai, Jimmy X. Tang, Ekambar R. Kandimalla, and Sudhir Agrawal. Idera Pharmaceuticals, Inc, 345 Vassar Street, Cambridge, MA 02139
Single-stranded viral RNAs have been shown as ligands for Toll-like receptor (TLR) 7 and/or TLR8. Previously we have designed novel structures of single-stranded oligoribonucleotides (ORN) containing two 5'-ends. These novel ORN, referred to as Stabilized Immune Modulatory RNA (SIMRA), are stable against nucleases and acted as agonists of TLR8 and 7. In the present study, we have designed and synthesized several ORN sequences with the ability to form intermolecular duplexes. Such novel ORN are more stable against nucleases because of the secondary structure. The new ORN that form secondary structures activated HEK293 cells expressing human TLR8, but not human TLR3 that is receptor for double-stranded RNA. The new ORN showed potent induction of cytokines and chemokines in human cell-based assays. The ORN that can form secondary structures are a novel class of TLR8 ligands.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007