De Angelis Marta, De Filippis Barbara, Balaha Marwa, Giampietro Letizia, Miteva Mariya Timotey, De Chiara Giovanna, Palamara Anna Teresa, Nencioni Lucia, Mollica Adriano
Laboratory Affiliated to Institute, Department of Public Health and Infectious Diseases, Pasteur Italia-Cenci Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy.
Department of Pharmacy, University "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy.
Pharmaceuticals (Basel). 2022 Aug 26;15(9):1061. doi: 10.3390/ph15091061.
Resveratrol (RSV) is a natural stilbene polyphenolic compound found in several plant species. It is characterized by antioxidant properties, and its role in controlling viral replication has been demonstrated for different viral infections. Despite its promising antiviral properties, RSV biological activity is limited by its low bioavailability and high metabolic rate. In this study, we optimized its structure by synthesizing new RSV derivatives that maintained the phenolic scaffold and contained different substitution patterns and evaluated their potential anti-influenza virus activity. The results showed that viral protein synthesis decreased 24 h post infection; particularly, the nitro-containing compounds strongly reduced viral replication. The molecules did not exert their antioxidant properties during infection; in fact, they were not able to rescue the virus-induced drop in GSH content or improve the antioxidant response mediated by the Nrf2 transcription factor and G6PD enzyme. Similar to what has already been reported for RSV, they interfered with the nuclear-cytoplasmic traffic of viral nucleoprotein, probably inhibiting cellular kinases involved in the regulation of specific steps of the virus life cycle. Overall, the data indicate that more lipophilic RSV derivatives have improved antiviral efficacy compared with RSV and open the way for new cell-targeted antiviral strategies.
白藜芦醇（RSV）是一种存在于多种植物中的天然芪类多酚化合物。它具有抗氧化特性，并且其在控制病毒复制方面的作用已在不同病毒感染中得到证实。尽管RSV具有有前景的抗病毒特性，但其生物活性受到低生物利用度和高代谢率的限制。在本研究中，我们通过合成保留酚类骨架并含有不同取代模式的新型RSV衍生物来优化其结构，并评估了它们潜在的抗流感病毒活性。结果表明，感染后24小时病毒蛋白合成减少；特别是，含硝基的化合物强烈降低了病毒复制。这些分子在感染期间未发挥其抗氧化特性；事实上，它们无法挽救病毒诱导的谷胱甘肽含量下降或改善由Nrf2转录因子和G6PD酶介导的抗氧化反应。与已报道的RSV情况类似，它们干扰了病毒核蛋白的核质运输，可能抑制了参与病毒生命周期特定步骤调控的细胞激酶。总体而言，数据表明与RSV相比，亲脂性更强的RSV衍生物具有更高的抗病毒效力，并为新的细胞靶向抗病毒策略开辟了道路。
