Shoji Masaki, Nakaoka Kensuke, Ishikawa Momiji, Kasai Yusuke, Esumi Tomoyuki, Takahashi Etsuhisa, Kido Hiroshi, Imawaga Hiroshi, Kuzuhara Takashi
Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
Chemistry of Functional Molecules, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
PLoS One. 2025 Aug 7;20(8):e0329964. doi: 10.1371/journal.pone.0329964. eCollection 2025.
Triethylamine (Et3N) is a proton (H⁺) acceptor that is widely used in various industrial organic synthesis processes, including the production of pharmaceuticals, agrochemicals, and polymers. Inhalation of high Et3N concentrations can damage human respiratory tract and lungs. Given the compound's known reactivity and membrane-penetrating properties, we hypothesized that non-toxic concentrations of Et₃N may exert modulatory effects on virus-host interactions in epithelial cells. We thus investigated the anti-influenza activity of Et3N and found that it enhanced the viability of influenza A H1N1 and H3N2 virus-infected Madin-Darby canine kidney (MDCK) cells. Non-cytotoxic Et3N concentrations reduced the number of infected cells and suppressed influenza A virus nucleoprotein expression as well as viral gene and antiviral host gene upregulation in infected MDCK cells. Selectivity index values of Et₃N against influenza A virus infection, ranging from approximately 10 to over 50. These findings indicated that Et3N inhibited influenza A H1N1 and H3N2 viral infections. Additionally, Et3N suppressed influenza A H1N1 and H3N2 virus titers in the infected MDCK cell culture supernatant, suggesting that it inhibited viral growth in infected cells. This implies that Et3N may suppress influenza A virus release and/or replication by targeting viral or host cell factors. However, Et3N did not inhibit influenza A viral neuraminidase or RNA-dependent RNA polymerase activity, which are involved in viral release and replication, respectively. These results suggest that Et3N targets other viral proteins or host cell factors essential for influenza A virus growth. Our findings demonstrate that Et3N exerts anti-influenza activity, providing new insights into the development of antiviral agents based on Et3N skeleton.
三乙胺（Et3N）是一种质子（H⁺）受体，广泛应用于各种工业有机合成过程，包括药物、农用化学品和聚合物的生产。吸入高浓度的Et3N会损害人类呼吸道和肺部。鉴于该化合物已知的反应活性和膜穿透特性，我们推测无毒浓度的Et₃N可能对上皮细胞中的病毒-宿主相互作用产生调节作用。因此，我们研究了Et3N的抗流感活性，发现它提高了甲型H1N1和H3N2流感病毒感染的麦迪逊-达比犬肾（MDCK）细胞的活力。非细胞毒性的Et3N浓度减少了感染细胞的数量，并抑制了甲型流感病毒核蛋白的表达以及感染的MDCK细胞中病毒基因和抗病毒宿主基因的上调。Et₃N对甲型流感病毒感染的选择性指数值约为10至50以上。这些发现表明Et3N抑制了甲型H1N1和H3N2流感病毒感染。此外，Et3N抑制了感染的MDCK细胞培养上清液中甲型H1N1和H3N2流感病毒的滴度，表明它抑制了感染细胞中的病毒生长。这意味着Et3N可能通过靶向病毒或宿主细胞因子来抑制甲型流感病毒的释放和/或复制。然而，Et3N并未抑制分别参与病毒释放和复制的甲型流感病毒神经氨酸酶或RNA依赖性RNA聚合酶的活性。这些结果表明Et3N靶向甲型流感病毒生长所必需的其他病毒蛋白或宿主细胞因子。我们的研究结果表明Et3N具有抗流感活性，为基于Et3N骨架的抗病毒药物开发提供了新的见解。
