title: Synthetic agonists of Toll-like receptors 7, 8 and 9.
abstract: TLRs (Toll-like receptors) are a family of innate immune receptors that induce protective immune responses against infections. Single-stranded viral RNA and bacterial DNA containing unmethylated CpG motifs are the ligands for TLR7 and TLR8 and 9 respectively. We have carried out extensive structure-activity relationship studies of DNA- and RNA-based compounds to elucidate the impact of nucleotide motifs and structures on these TLR-mediated immune responses. These studies have led us to design novel DNA- and RNA-based compounds, which act as potent agonists of TLR9 and TLR7 and 8 respectively. These novel synthetic agonists produce different immune response profiles depending on the structures and nucleotide motifs present in them. The ability to modulate TLR-mediated immune responses with these novel DNA- and RNA-based agonists in a desired fashion may allow targeting a broad range of diseases, including cancers, asthma, allergies and infections, alone or in combination with other therapeutic agents, and their use as adjuvants with vaccines. IMO-2055, our first lead candidate, is a TLR9 agonist that is currently in clinical evaluation in oncology patients. A second candidate, IMO-2125, is also a TLR9 agonist that has been shown to induce high and sustained levels of IFN (interferon) in non-human primates and is being evaluated in HepC-infected human subjects.
authors.affiliation: Idera Pharmaceuticals, 167 Sidney Street, Cambridge, MA 02139, USA. sagrawal@iderapharma.com
authors.forename: S
authors.initials: S
authors.lastname: Agrawal
authors.forename: E R
authors.initials: ER
authors.lastname: Kandimalla
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000276:immunology; D004269:DNA, Bacterial / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007372:Interferons / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D012367:RNA, Viral / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000276:immunology
chemical_list: D004269:DNA, Bacterial; D008024:Ligands; D012367:RNA, Viral; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D007372:Interferons