Sornprasert Suthatta, Jaratsittisin Janejira, Chumchanchira Chanida, Smith Duncan R
Institute of Molecular Biosciences, Center for Advanced Therapeutics, Mahidol University, Nakhon Pathom, 73170, Thailand.
Phd Degree Program in Biology, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand.
Sci Rep. 2025 Mar 28;15(1):10731. doi: 10.1038/s41598-025-95346-7.
Fatty acid synthase (FASN) has been shown to be critical in the replication of several viruses of the genus Orthoflavivirus. In this study the role two inhibitors of FASN that work through different mechanisms were investigated in dengue virus (DENV) and Zika virus (ZIKV) infections. Triclosan is a FASN inhibitor that targets the enol reductase domain of FASN, while lapatinib exerts an effect on FASN through acting on HER2, an upstream regulator of FASN. After determining cytotoxicity, a comprehensive analysis of the effect of these drugs in DENV 2 and ZIKV infection was undertaken. The results showed that triclosan had moderate antiviral activity against both DENV 2 (EC = 10.21 µM; Selective index (SI) = 3.99) and ZIKV ( EC = 22.84 µM; SI = 5.49). Lapatinib had reasonable activity against DENV 2 (EC = 4.9 µM; SI = 26.09), but computer modeling suggested that lapatinib had the potential to be a directly acting antiviral by binding to NS5. The result of that analysis suggested that lapatinib was a better fit with ZIKV NS5 than DENV NS5, and this was confirmed as the EC for lapatinib towards ZIKV was was 2 µM and the calculated SI was 37.92. The results of triclosan are consistent with other studies that use inhibitors that target other domains of FASN, suggesting that simply targeting the enzymatic activity of FASN is insufficient for therapeutic drug development, but that lapatinib, or similar molecules may have real therapeutic potential.
脂肪酸合酶（FASN）已被证明在几种黄病毒属病毒的复制中起关键作用。在本研究中，研究了两种通过不同机制起作用的FASN抑制剂在登革热病毒（DENV）和寨卡病毒（ZIKV）感染中的作用。三氯生是一种FASN抑制剂，靶向FASN的烯醇还原酶结构域，而拉帕替尼通过作用于FASN的上游调节因子HER2对FASN产生影响。在确定细胞毒性后，对这些药物在DENV 2和ZIKV感染中的作用进行了全面分析。结果表明，三氯生对DENV 2（EC = 10.21 µM；选择性指数（SI）= 3.99）和ZIKV（EC = 22.84 µM；SI = 5.49）均具有中等抗病毒活性。拉帕替尼对DENV 2具有合理的活性（EC = 4.9 µM；SI = 26.09），但计算机模拟表明，拉帕替尼有可能通过与NS5结合而成为一种直接作用的抗病毒药物。该分析结果表明，拉帕替尼与ZIKV NS5的契合度优于DENV NS5，这一点得到了证实，因为拉帕替尼对ZIKV的EC为2 µM，计算得出的SI为37.92。三氯生的结果与其他使用靶向FASN其他结构域的抑制剂的研究一致，表明仅靶向FASN的酶活性对于治疗药物开发是不够的，但拉帕替尼或类似分子可能具有真正的治疗潜力。
