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

• Published in: Antiviral research 2016-05, Vol.129, p.81-92
• Main Authors: Yamada, Hiroshi, Nagase, Satoshi, Takahashi, Kazuo, Sakoda, Yoshihiro, Kida, Hiroshi, Okamoto, Shigefumi
• Format: Article
• Language: English
• Subjects: 430-Loop in neuraminidase; Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Survival - drug effects; Dogs; G-tetrad formation; HEK293 Cells; Humans; Influenza A virus; Influenza A virus - drug effects; Influenza A virus - growth & development; Influenza A virus - physiology; Ligands; Lung - virology; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred BALB C; Neuraminidase - antagonists & inhibitors; Neuraminidase - chemistry; Neuraminidase - genetics; Neuraminidase inhibitors; Oligodeoxynucleotide D35; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - chemical synthesis; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - pharmacology; Oseltamivir - pharmacology; Toll-Like Receptor 9 - chemistry; Toll-Like Receptor 9 - immunology; Toll-Like Receptor 9 - metabolism; Virus Release - drug effects; Virus Replication - drug effects
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2016.02.012

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 contributse 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. •The oligodeoxynucleotide D35 suppressed replication of some influenza A viruses.•D35 inhibits viral replication at the late step which is dependent on NA activity.•Antiviral mechanism by D35 is different from that by oseltamivir.