Department of Agricultural Microbiology, Faculty of Agriculture, Cairo University, Giza, 12613, Giza District, Egypt.
Department of Biology, Adham University College, Umm Al-Qura University, 21955, Makkah, Saudi Arabia.
BMC Complement Med Ther. 2024 Jan 22;24(1):49. doi: 10.1186/s12906-023-04303-2.
The continuous evolution of drug-resistant influenza viruses highlights the necessity for repurposing naturally-derived and safe phytochemicals with anti-influenza activity as novel broad-spectrum anti-influenza medications.
In this study, nitrogenous alkaloids were tested for their viral inhibitory activity against influenza A/H1N1 and A/H5N1 viruses. The cytotoxicity of tested alkaloids on MDCK showed a high safety range (CC > 200 µg/ml), permitting the screening for their anti-influenza potential.
Herein, atropine sulphate, pilocarpine hydrochloride and colchicine displayed anti-H5N1 activities with IC values of 2.300, 0.210 and 0.111 µg/ml, respectively. Validation of the IC values was further depicted by testing the three highly effective alkaloids, based on their potent IC values against seasonal influenza A/H1N1 virus, showing comparable IC values of 0.204, 0.637 and 0.326 µg/ml, respectively. Further investigation suggests that colchicine could suppress viral infection by primarily interfering with IAV replication and inhibiting viral adsorption, while atropine sulphate and pilocarpine hydrochloride could directly affect the virus in a cell-free virucidal effect. Interestingly, the in silico molecular docking studies suggest the abilities of atropine, pilocarpine, and colchicine to bind correctly inside the active sites of the neuraminidases of both influenza A/H1N1 and A/H5N1 viruses. The three alkaloids exhibited good binding energies as well as excellent binding modes that were similar to the co-crystallized ligands. On the other hand, consistent with in vitro results, only colchicine could bind correctly against the M2-proton channel of influenza A viruses (IAVs). This might explicate the in vitro antiviral activity of colchicine at the replication stage of the virus replication cycle.
This study highlighted the anti-influenza efficacy of biologically active alkaloids including colchicine. Therefore, these alkaloids should be further characterized in vivo (preclinical and clinical studies) to be developed as anti-IAV agents.
耐药流感病毒的不断进化突出了将具有抗流感活性的天然衍生和安全的植物化学物质重新用于新型广谱抗流感药物的必要性。
在这项研究中，测试了氮生物碱对甲型流感病毒/H1N1 和甲型流感病毒/H5N1 的病毒抑制活性。测试生物碱对 MDCK 的细胞毒性显示出高安全性范围（CC>200μg/ml），允许筛选其抗流感潜力。
在此，硫酸阿托品、盐酸毛果芸香碱和秋水仙碱对 H5N1 的抑制活性分别为 2.300、0.210 和 0.111μg/ml。根据它们对季节性甲型流感病毒/H1N1 的强大 IC 值，进一步验证了三个高效生物碱的 IC 值，显示出相当的 IC 值，分别为 0.204、0.637 和 0.326μg/ml。进一步的研究表明，秋水仙碱可以通过主要干扰 IAV 复制和抑制病毒吸附来抑制病毒感染，而硫酸阿托品和盐酸毛果芸香碱可以通过细胞外病毒杀伤作用直接影响病毒。有趣的是，计算机分子对接研究表明，阿托品、毛果芸香碱和秋水仙碱能够正确结合到甲型流感病毒/H1N1 和甲型流感病毒/H5N1 病毒的神经氨酸酶的活性部位。这三种生物碱都表现出良好的结合能和与共结晶配体相似的优异结合模式。另一方面，与体外结果一致，只有秋水仙碱能够正确结合到流感病毒的 M2-质子通道上。这可能解释了秋水仙碱在病毒复制周期的复制阶段的体外抗病毒活性。
本研究强调了包括秋水仙碱在内的具有生物活性的生物碱的抗流感功效。因此，这些生物碱应该在体内（临床前和临床研究）进一步表征，以开发为抗 IAV 药物。
