College of Chemistry and Pharmacy, Northwest A&F University, Xianyang 712100, China.
College of Veterinary Medicine, Northwest A&F University, Xianyang 712100, China.
Biomolecules. 2021 Nov 12;11(11):1687. doi: 10.3390/biom11111687.
Newcastle disease virus (NDV) is one of the highly contagious pathogens causing devastating economic effects on the global poultry industry. In the present study, three 1-formyl--carboline derivatives (compounds , , and ) were found to be potent inhibitors of different genotypes of NDV with IC values within 10 μM, which are similar to ribavirin. The virus titers were decreased by the presence of 1-formyl--carboline derivatives in a dose-dependent manner, and the inhibition rate was found to exceed 90% at the concentration of 20 μM. These compounds mainly suppressed the adsorption and entry processes of NDV lifecycle. Through DARTS, CETSA, and RBC binding assay, these compounds were identified as novel HN inhibitors, which could directly interact with the NDV HN protein to affect the adsorption of NDV. Furthermore, they could inhibit the entry of NDV through suppressing the PI3K/Akt pathway rather than the ERK pathway. The PI3K/Akt pathway was proved to be involved in NDV entry. Our findings reveal a unique mechanism through which 1-formyl--carboline derivatives restrain NDV infection. Moreover, these compounds represent suitable scaffolds for designing novel HN inhibitors.
新城疫病毒（NDV）是一种高度传染性病原体，对全球家禽业造成了毁灭性的经济影响。在本研究中，发现三种 1-甲酰基-卡波啉衍生物（化合物 、 和 ）对不同基因型的 NDV 具有很强的抑制作用，其 IC 值在 10 μM 以内，与利巴韦林相当。病毒滴度随 1-甲酰基-卡波啉衍生物浓度呈剂量依赖性下降，在 20 μM 浓度下抑制率超过 90%。这些化合物主要抑制 NDV 生命周期的吸附和进入过程。通过 DARTS、CETSA 和 RBC 结合试验，这些化合物被鉴定为新型 HN 抑制剂，可直接与 NDV HN 蛋白相互作用，影响 NDV 的吸附。此外，它们可以通过抑制 PI3K/Akt 通路而不是 ERK 通路来抑制 NDV 的进入。PI3K/Akt 通路被证明参与了 NDV 的进入。我们的研究结果揭示了 1-甲酰基-卡波啉衍生物抑制 NDV 感染的独特机制。此外，这些化合物为设计新型 HN 抑制剂提供了合适的骨架。
