School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 100, Taiwan.
Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan.
Eur J Med Chem. 2022 May 5;235:114295. doi: 10.1016/j.ejmech.2022.114295. Epub 2022 Mar 19.
Niclosamide, a widely-used anthelmintic drug, inhibits SARS-CoV-2 virus entry through TMEM16F inhibition and replication through autophagy induction, but the relatively high cytotoxicity and poor oral bioavailability limited its application. We synthesized 22 niclosamide analogues of which compound 5 was found to exhibit the best anti-SARS-CoV-2 efficacy (IC = 0.057 μ M) and compounds 6, 10, and 11 (IC = 0.39, 0.38, and 0.49 μ M, respectively) showed comparable efficacy to niclosamide. On the other hand, compounds 5, 6, 11 contained higher stability in human plasma and liver S9 enzymes assay than niclosamide, which could improve bioavailability and half-life when administered orally. Fluorescence microscopy revealed that compound 5 exhibited better activity in the reduction of phosphatidylserine externalization compared to niclosamide, which was related to TMEM16F inhibition. The AI-predicted protein structure of human TMEM16F protein was applied for molecular docking, revealing that 4'-NO of 5 formed hydrogen bonding with Arg809, which was blocked by 2'-Cl in the case of niclosamide.
硝氯酚，一种广泛使用的驱虫药，通过抑制 TMEM16F 来抑制 SARS-CoV-2 病毒进入，通过诱导自噬来抑制复制，但相对较高的细胞毒性和较差的口服生物利用度限制了其应用。我们合成了 22 种硝氯酚类似物，其中化合物 5 表现出最好的抗 SARS-CoV-2 功效（IC = 0.057 μM），化合物 6、10 和 11（IC = 0.39、0.38 和 0.49 μM）与硝氯酚相比具有相当的功效。另一方面，化合物 5、6、11 在人血浆和肝 S9 酶测定中比硝氯酚具有更高的稳定性，这可以提高口服给药时的生物利用度和半衰期。荧光显微镜显示，与硝氯酚相比，化合物 5 在减少磷脂酰丝氨酸外化方面表现出更好的活性，这与 TMEM16F 抑制有关。应用人工智能预测的人 TMEM16F 蛋白的蛋白质结构进行分子对接，结果表明 5 的 4'-NO 与 Arg809 形成氢键，而硝氯酚中 2'-Cl 则阻止了这种氢键的形成。
