title: Toll-like receptor 9 ligand D-type oligodeoxynucleotide D35 as a broad inhibitor for influenza A virus replication that is associated with suppression of neuraminidase activity.
abstract: The most effective drugs available to treat influenza are neuraminidase (NA) inhibitors, which provide important additional measures for the control of influenza virus infections. However, since the emergence of NA inhibitor-resistant viruses may compromise the clinical utility of this class of anti-influenza agents, it is very important to develop new anti-influenza agents which target a different region in NA responsible for its sensitivity from that for NA inhibitors and could be used to treat NA inhibitors-resistant isolates. The oligodeoxynucleotide D35, multimerized and aggregated, suppressed replication of influenza A viruses except A/WSN/33 (WSN). The suppressive viral replication by D35 depended on G-terad and multimer formation. The range of the suppressive viral replication at the late stage, including virus assembly and release from infected cells, was much larger than that at the initial stage, viral attachment and entry. D35 suppressed NA activity of influenza A viruses. Furthermore, replacing the NA gene of A/Puerto Rico/8/34 (PR8), in which viral replication was inhibited by D35 at the late stage, with the NA gene from WSN, in which viral replication was not inhibited, eliminated the D35-dependent suppression. D35 showed an additive anti-influenza effect with oseltamivir. It was also effective in vivo. These results suggest that the influenza virus NA mainly contributes to the D35-suppressible virus release from infected cells at the late stage. In addition, because administration of D35 into the virus-infected mice suppressed viral replication and weight loss, clinical application of D35 could be considered.
authors.affiliation: Laboratory of Virology and Vaccinology, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Laboratory Sciences, Division of Health Sciences, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagase
authors.affiliation: Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Laboratory of Microbiology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Laboratory of Microbiology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan; Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Department of Laboratory Sciences, Division of Health Sciences, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. Electronic address: sokamoto@mhs.mp.kanazawa-u.ac.jp.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Okamoto
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D008024:Ligands; D008168:Lung / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053139:Oseltamivir / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D057074:Virus Release / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D053139:Oseltamivir; D009439:Neuraminidase
keywords: 430-Loop in neuraminidase; G-tetrad formation; Influenza A virus; Neuraminidase inhibitors; Oligodeoxynucleotide D35