Novel Small Molecule Targeting the Hemagglutinin Stalk of Influenza Viruses

Jin Il Kim, Sangmoo Lee, Gong Yeal Lee, Sehee Park, Joon Yong Bae, Jun Heo, Hong Youb Kim, Seok Hun Woo, Hae Un Lee, Chung Am Ahn, Hye Jin Bang, Hyun Soo Ju, Kiwon Ok, Youngjoo Byun, Dae Jin Cho, Jae Soo Shin, Dong Yeon Kim, Mee Sook Park, Man-Seong Park

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalJournal of virology
Volume93
Issue number17
DOIs
Publication statusPublished - 2019 Sep 1

Fingerprint

Hemagglutinins
hemagglutinins
Orthomyxoviridae
influenza
Human Influenza
drugs
Pharmaceutical Preparations
H1N1 Subtype Influenza A Virus
Membrane Fusion
Virus Diseases
Vaccines
Influenza B virus
High-Throughput Screening Assays
vaccines
antiviral agents
Oseltamivir
sialidase
new drugs
mice
Neuraminidase

Keywords

  • antiviral agents
  • hemagglutinin stalk
  • influenza virus
  • membrane fusion
  • small molecule

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Novel Small Molecule Targeting the Hemagglutinin Stalk of Influenza Viruses. / Kim, Jin Il; Lee, Sangmoo; Lee, Gong Yeal; Park, Sehee; Bae, Joon Yong; Heo, Jun; Kim, Hong Youb; Woo, Seok Hun; Lee, Hae Un; Ahn, Chung Am; Bang, Hye Jin; Ju, Hyun Soo; Ok, Kiwon; Byun, Youngjoo; Cho, Dae Jin; Shin, Jae Soo; Kim, Dong Yeon; Park, Mee Sook; Park, Man-Seong.

In: Journal of virology, Vol. 93, No. 17, 01.09.2019.

Research output: Contribution to journalArticle

Kim, JI, Lee, S, Lee, GY, Park, S, Bae, JY, Heo, J, Kim, HY, Woo, SH, Lee, HU, Ahn, CA, Bang, HJ, Ju, HS, Ok, K, Byun, Y, Cho, DJ, Shin, JS, Kim, DY, Park, MS & Park, M-S 2019, 'Novel Small Molecule Targeting the Hemagglutinin Stalk of Influenza Viruses', Journal of virology, vol. 93, no. 17. https://doi.org/10.1128/JVI.00878-19
Kim, Jin Il ; Lee, Sangmoo ; Lee, Gong Yeal ; Park, Sehee ; Bae, Joon Yong ; Heo, Jun ; Kim, Hong Youb ; Woo, Seok Hun ; Lee, Hae Un ; Ahn, Chung Am ; Bang, Hye Jin ; Ju, Hyun Soo ; Ok, Kiwon ; Byun, Youngjoo ; Cho, Dae Jin ; Shin, Jae Soo ; Kim, Dong Yeon ; Park, Mee Sook ; Park, Man-Seong. / Novel Small Molecule Targeting the Hemagglutinin Stalk of Influenza Viruses. In: Journal of virology. 2019 ; Vol. 93, No. 17.
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AU - Kim, Jin Il

AU - Lee, Sangmoo

AU - Lee, Gong Yeal

AU - Park, Sehee

AU - Bae, Joon Yong

AU - Heo, Jun

AU - Kim, Hong Youb

AU - Woo, Seok Hun

AU - Lee, Hae Un

AU - Ahn, Chung Am

AU - Bang, Hye Jin

AU - Ju, Hyun Soo

AU - Ok, Kiwon

AU - Byun, Youngjoo

AU - Cho, Dae Jin

AU - Shin, Jae Soo

AU - Kim, Dong Yeon

AU - Park, Mee Sook

AU - Park, Man-Seong

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N2 - 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.

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