Salinomycin Inhibits Influenza Virus Infection by Disrupting Endosomal Acidification and Viral Matrix Protein 2 Function

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

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Author(s)

  • Yejin Jang
  • Jin Soo Shin
  • Yi-Seul Yoon
  • Hye Won Lee
  • Oh Seung Kwon
  • Sehee Park
  • Man-Seong Park
  • Meehyein Kim

Detail(s)

Original languageEnglish
Article numbere0144118
Journal / PublicationJournal of Virology
Volume92
Issue number24
Online published27 Nov 2018
Publication statusPublished - Dec 2018
Externally publishedYes

Abstract

Screening of chemical libraries with 2,000 synthetic compounds identified salinomycin as a hit against influenza A and B viruses, with 50% effective concentrations ranging from 0.4 to 4.3 M in cells. This compound is a carboxylic polyether ionophore that exchanges monovalent ions for protons across lipid bilayer membranes. Monitoring the time course of viral infection showed that salinomycin blocked nuclear migration of viral nuclear protein (NP), the most abundant component of the viral ribonucleoprotein (vRNP) complex. It caused cytoplasmic accumulation of NP, particularly within perinuclear endosomes, during virus entry. This was primarily associated with failure to acidify the endosomal-lysosomal compartments. Similar to the case with amantadine (AMT), proton channel activity of viral matrix protein 2 (M2) was blocked by salinomycin. Using purified retroviral Gag-based virus-like particles (VLPs) with M2, it was proved that salinomycin directly affects the kinetics of a proton influx into the particles but in a manner different from that of AMT. Notably, oral administration of salinomycin together with the neuraminidase inhibitor oseltamivir phosphate (OSV-P) led to enhanced antiviral effect over that with either compound used alone in influenza A virus-infected mouse models. These results provide a new paradigm for developing antivirals and their combination therapy that control both host and viral factors. IMPORTANCE Influenza virus is a main cause of viral respiratory infection in humans as well as animals, occasionally with high mortality. Circulation of influenza viruses resistant to the matrix protein 2 (M2) inhibitor, amantadine, is highly prevalent. Moreover, the frequency of detection of viruses resistant to the neuraminidase inhibitors, including oseltamivir phosphate (OSV-P) or zanamivir, is also increasing. These issues highlight the need for discovery of new antiviral agents with different mechanisms. Salinomycin as the monovalent cation-proton antiporter exhibited consistent inhibitory effects against influenza A and B viruses. It plays multifunctional roles by blocking endosomal acidification and by inactivating the proton transport function of M2, the key steps for influenza virus uncoating. Notably, salinomycin resulted in marked therapeutic effects in influenza virus-infected mice when combined with OSV-P, suggesting that its chemical derivatives could be developed as an adju-vant antiviral therapy to treat influenza infections resistant or less sensitive to existing drugs.

Research Area(s)

  • Antiviral agent, Combination treatment, Influenza virus, Ionophore, M2 ion channel, Salinomycin

Citation Format(s)

Salinomycin Inhibits Influenza Virus Infection by Disrupting Endosomal Acidification and Viral Matrix Protein 2 Function. / Jang, Yejin; Shin, Jin Soo; Yoon, Yi-Seul; Go, Yun Young; Lee, Hye Won; Kwon, Oh Seung; Park, Sehee; Park, Man-Seong; Kim, Meehyein.

In: Journal of Virology, Vol. 92, No. 24, e0144118, 12.2018.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal