title: DNA-based strategies for blocking HMGB1 cytokine activity: design, synthesis and preliminary in vitro/in vivo assays of DNA and DNA-like duplexes.
abstract: In this work we report the design and synthesis of kinked oligonucleotide duplexes as potential inhibitors of HMGB1, a cytokine which triggers a broad range of immunological effects. We found that the designed ligands can interact with HMGB1, as evidenced by circular dichroism spectroscopy, and are able to block some extracellular effects induced by the protein, such as cellular proliferation and migration, as we demonstrated by in vitro biological assays. After selecting the most stable and active kinked duplex, we synthesized the corresponding PNA/DNA chimeric duplex which resulted to be more resistant to enzymatic degradation, and showed a biological activity comparable to that of the natural duplex. Preliminary in vivo assays in a mouse inflammatory model, showed a significant decrease of the mortality after administration of the PNA/DNA kinked duplex to LPS-treated mice.
authors: Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy. domymusu@alice.it
authors: Domenica
authors: D
authors: Musumeci
authors: Enrico M
authors: EM
authors: Bucci
authors: Giovanni N
authors: GN
authors: Roviello
authors: Roberto
authors: R
authors: Sapio
authors: Margherita
authors: M
authors: Valente
authors: Maria
authors: M
authors: Moccia
authors: Marco E
authors: ME
authors: Bianchi
authors: Carlo
authors: C
authors: Pedone
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004270:DNA, Circular; D019446:Endotoxemia / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020135:Peptide Nucleic Acids / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015996:Survival Rate; D013997:Time Factors
chemical_list: D004270:DNA, Circular; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D009692:Nucleic Acid Heteroduplexes; D020135:Peptide Nucleic Acids; C015314:kinked DNA; D004247:DNA