Novel Small Molecule Targeting the Hemagglutinin Stalk of Influenza Viruses
| Autor: | Hyun Soo Ju, Sehee Park, Mee Sook Park, Dong Yeon Kim, Kiwon Ok, Jun Heo, Jae Soo Shin, Hong Youb Kim, Youngjoo Byun, Chung Am Ahn, Hae Un Lee, Hye Jin Bang, Joon Yong Bae, Man Seong Park, Dae Jin Cho, Sangmoo Lee, Jin Il Kim, Seok Hun Woo, Gong Yeal Lee |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Oseltamivir
Immunology Hemagglutinin (influenza) Hemagglutinin Glycoproteins Influenza Virus Biology Virus Replication Membrane Fusion Microbiology Virus Madin Darby Canine Kidney Cells law.invention Small Molecule Libraries Mice 03 medical and health sciences chemistry.chemical_compound Dogs Influenza A Virus H1N1 Subtype Orthomyxoviridae Infections In vivo law Virology Vaccines and Antiviral Agents Chlorocebus aethiops Viral neuraminidase Animals Humans Vero Cells 030304 developmental biology 0303 health sciences 030306 microbiology virus diseases Lipid bilayer fusion Disease Models Animal chemistry Viral replication Influenza Vaccines Insect Science Mutation biology.protein Recombinant DNA Female |
| Zdroj: | Journal of Virology. 93 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00878-19 |
| Popis: | Combating influenza is one of the perennial global public health issues to be managed. Antiviral drugs are useful for the treatment of influenza in the absence of an appropriate vaccine. However, the appearance of resistant strains necessitates a constant search for new drugs. In this study, we investigated novel anti-influenza drug candidates using in vitro and in vivo assays. We identified anti-influenza hit compounds using a high-throughput screening method with a green fluorescent protein-tagged recombinant influenza virus. Through subsequent analyses of their cytotoxicity and pharmacokinetic properties, one candidate (IY7640) was selected for further evaluation. In a replication kinetics analysis, IY7640 showed greater inhibitory effects during the early phase of viral infection than the viral neuraminidase inhibitor oseltamivir. In addition, we observed that hemagglutinin (HA)-mediated membrane fusion was inhibited by IY7640 treatment, indicating that the HA stalk region, which is highly conserved across various (sub)types of influenza viruses, may be the molecular target of IY7640. In an escape mutant analysis in cells, amino acid mutations were identified at the HA stalk region of the 2009 pandemic H1N1 (pH1N1) virus. Even though the in vivo efficacy of IY7640 did not reach complete protection in a lethal challenge study in mice, these results suggest that IY7640 has potential to be developed as a new type of anti-influenza drug. IMPORTANCE Anti-influenza drugs with broad-spectrum efficacy against antigenically diverse influenza viruses can be highly useful when no vaccines are available. To develop new anti-influenza drugs, we screened a number of small molecules and identified a strong candidate, IY7640. When added at the time of or after influenza virus infection, IY7640 was observed to successfully inhibit or reduce viral replication in cells. We subsequently discovered that IY7640 targets the stalk region of the influenza HA protein, which exhibits a relatively high degree of amino acid sequence conservation across various (sub)types of influenza viruses. Furthermore, IY7640 was observed to block HA-mediated membrane fusion of H1N1, H3N2, and influenza B viruses in cells. Although it appears less effective against strains other than H1N1 subtype viruses in a challenge study in mice, we suggest that the small molecule IY7640 has potential to be optimized as a new anti-influenza drug. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|