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Front. Pharmacol. | doi: 10.3389/fphar.2019.01025

Toosendanin from Melia Fructus Suppresses Influenza A Virus infection by Altering Nuclear Localization of Viral Polymerase PA Protein

 Young-Hee Jin1*, Sun Oh Kwon2,  Jang-gi Choi3,  Won-Kyung Cho3, Bonggi Lee3 and  Jin Yeul Ma3
  • 1Korea Institute of Oriental Medicine, South Korea
  • 2CEVI, Korea Institute of Oriental Medicine (KIOM), South Korea
  • 3Korean Medicine Application Center, Korea Institute of Oriental Medicine (KIOM), South Korea

Toosendanin (TSN) is a major bioactive component of Melia Fructus (MF) with anti-inflammatory, anti-botulinum, anti-microbial, and analgesic efficacy. Our previous study demonstrated that MF has anti-influenza A virus activity; however, the contribution of TSN is still unclear. In this study, we found that TSN suppressed influenza A virus infection when administered before or concurrent with the virus, but not after infection. TSN pretreatment inhibited viral hemagglutinin (HA), nucleoprotein (NP), polymerase acidic (PA) protein, and matrix protein 2 (M2) mRNA synthesis as well as NP, PA, M2, and nonstructural protein 1 (NS1) expression, but had no effect on HA or neuraminidase (NA) activity. In addition, TSN induced cytoplasmic location of PA protein disrupting nuclear translocation. Docking simulation suggested that the binding affinity of TSN to PA protein may be stronger than that of a known PA protein inhibitor. Pretreatment with TSN also suppressed the infection-induced phospho-AKT expression but not the host immune response. Oral pretreatment with TSN enhanced the survival of infected mice. These results suggest that TSN inhibits influenza A virus infection at an early stage by altering PA protein nuclear localization. Thus, TSN may be a promising candidate for anti-influenza agent targeting the PA protein of the influenza A virus RNA polymerase complex.

Keywords: Toosendanin, Melia Fructus, Influenza A virus, Polymerase acidic protein, Anti-viral activity

Received: 23 May 2019; Accepted: 12 Aug 2019.

Edited by:

Pascale Cohen, Université Claude Bernard Lyon 1, France

Reviewed by:

Luis Martinez-Sobrido, University of Rochester, United States
Rong Hai, University of California, Riverside, United States  

Copyright: © 2019 Jin, Kwon, Choi, Cho, Lee and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Young-Hee Jin, Korea Institute of Oriental Medicine, Daejeon, South Korea, jinohee@kiom.re.kr