Synthesis and biological evaluation of novel coumarin derivatives in rhabdoviral clearance
Synthesis and biological evaluation of novel coumarin derivatives in rhabdoviral clearance
复制标题
DOI：
10.1016/j.ejmech.2021.113739
复制
发表时间：
2021-08-07
影响因子：
6.7
通讯作者：
Chen, Jiong
中科院分区：
文献类型：
--
作者：
Hu, Yang;Shan, Lipeng;Chen, Jiong
弹状病毒引起的疾病对整个人类的生产生活产生了巨大影响。主要问题是缺乏治疗这一病毒家族的药物。传染性造血细胞坏死病毒（Infectious hematopoietic necrosis virus，IHNV）是一种典型的弹状病毒，是引起IHN的病原，给鲑鱼养殖业造成了巨大的损失。因此，本研究以IHNV为模型，对35种新型香豆素衍生物的抗病毒活性进行了评价。在比较了四种筛选的候选衍生物在丘疹性上皮瘤鲤（EPC）细胞中的半数最大抑制浓度（IC 50）后，特别选择香豆素A9进行进一步验证研究，因为其对IHNV的IC 50值为2.96 μ M。结果表明，A9处理可显著抑制病毒诱导的EPC细胞病变效应（CPE）。此外，A9对另外两种弹状病毒，即鲤鱼春季病毒血症病毒和大口黑鲈弹状病毒的IC 50值分别为1.68和2.12 μ M。此外，我们的研究结果表明，A9发挥抗病毒活性，但不是通过破坏病毒颗粒和干扰IHNV的吸附。此外，我们发现A9对IHNV诱导的EPC细胞凋亡具有抑制作用，这反映在对细胞肿胀的保护、凋亡小体的形成以及细胞形态和核分裂的丧失。与IHNV组相比，A9治疗组的凋亡细胞数量减少了19.05%。此外，酶活性测定证明，A9抑制caspase 3，8和9的表达。这些结果表明，A9抑制病毒复制，在一定程度上，通过阻断IHNV诱导的细胞凋亡。在体内研究中，A9通过显著提高存活率而在病毒感染的鱼中表现出抗弹状病毒效果。与上述结果一致，A9在病毒感染的早期阶段抑制病毒敏感组织（脑、肾和脾）中的IHNV基因表达。重要的是，数据显示，在静态同居攻击模型中，A9降低了IHNV的水平传播，特别是在接受浴处理的鱼中，这表明A9可能是水产养殖中IHNV的合适治疗剂。因此，香豆素衍生物可被开发为抗弹状病毒的抗病毒剂。(C)2021年Elsevier Masson SAS。All rights reserved.
Diseases caused by rhabdoviruses have had a huge impact on the productive lives of the entire human population. The main problem is the lack of drugs for the treatment of this family of viruses. Infectious hematopoietic necrosis virus (IHNV), the causative agent of IHN, is a typical rhabdovirus which has caused huge losses to the salmonid industry. Therefore, in this study, IHNV was studied as a model to evaluate the antiviral activity of 35 novel coumarin derivatives. Coumarin A9 was specifically selected for further validation studies upon comparing the half maximum inhibitory concentration (IC50) of four screened candidate derivatives in epithelioma papulosum cyprinid (EPC) cells, as it exhibited an IC50 value of 2.96 mu M against IHNV. The data revealed that A9 treatment significantly suppressed the virus-induced cytopathic effect (CPE) in EPC cells. In addition, A9 showed IC50 values of 1.68 and 2.12 mu M for two other rhabdoviruses, spring viremia of carp virus and micropterus salmoides rhabdovirus, respectively. Furthermore, our results suggest that A9 exerts antiviral activity, but not by destroying the virus particles and interfering with the adsorption of IHNV. Moreover, we found that A9 had an inhibitory effect on IHNV-induced apoptosis in EPC cells, as reflected by the protection against cell swelling, formation of apoptotic bodies, and loss of cell morphology and nuclear division. There was a 19.05 % reduction in the number of apoptotic cells in the A9 treatment group compared with that in the IHNV group. In addition, enzyme activity assays proved that A9 suppressed the expression of caspase 3, 8 and 9. These results suggested that A9 inhibit viral replication, to some extent, by blocking IHNV-induced apoptosis. In an in vivo study, A9 exhibited an anti-rhabdovirus effect in virus-infected fish by substantially enhancing the survival rate. Consistent with the above results, A9 repressed IHNV gene expression in virus-sensitive tissues (brain, kidney and spleen) in the early stages of virus infection. Importantly, the data showed that horizontal transmission of IHNV was reduced by A9 in a static cohabitation challenge model, especially in fish that underwent bath treatment, suggesting that A9 might be a suitable therapeutic agent for IHNV in aquaculture. Therefore, coumarin derivatives can be developed as antiviral agents against rhabdoviruses. (C) 2021 Elsevier Masson SAS. All rights reserved.