Synthesized Magnolol Derivatives Improve Anti-Micropterus salmoides Rhabdovirus (MSRV) Activity In Vivo.
Synthesized Magnolol Derivatives Improve Anti-Micropterus salmoides Rhabdovirus (MSRV) Activity In Vivo.
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DOI：
10.3390/v14071421
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发表时间：
2022-06-28
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大口黑鲈弹状病毒（Micropterus salmoides rhabdovirus，MSRV）是大口黑鲈养殖中的主要病毒病原，每年给养殖业造成巨大的经济损失。目前，没有批准的药物用于治疗和控制这种病毒。本课题组前期工作从多种中药中筛选出厚朴，并分离鉴定了厚朴酚作为其抗包括MSRV在内的多种弹状病毒的主要活性成分。根据厚朴酚的构效关系和药效团模型，设计并合成了两种新的厚朴酚衍生物：氢化厚朴酚和2，2 ′-二甲氧基厚朴酚。系统地研究了它们在体外和体内的抗MSRV活性。通过比较半最大抑制浓度（IC 50），发现氢化厚朴酚的抗MSRV活性高于厚朴酚和2，2 ′-二甲氧基厚朴酚，IC 50为13.37 μM。氢化厚朴酚对草鱼卵巢（GCO）细胞具有保护作用，其作用机制可能与降低MSRV引起的细胞病变有关。进一步的研究表明，氢化厚朴酚不直接影响病毒体或干扰MSRV吸附。它在病毒复制期的6-8小时内起作用。用厚朴酚和氢化厚朴酚对MSRV感染进行体内治疗表明，与MSRV感染组相比，它们的存活率分别显着提高了44.6%和62.7%。当以20 mg/kg的剂量腹膜内注射鱼时，通过包括肝、脾和肾在内的器官中的病毒糖蛋白的表达测量的病毒载量也显著降低。总之，通过氢化的丙烯基团的厚朴酚的结构优化增加其抗MSRV活性在体外和体内。这些结果可为水产养殖中抗MSRV药物的发现和开发提供有价值的参考。
Micropterus salmoides rhabdovirus (MSRV) is a primary viral pathogen in largemouth bass aquaculture, which leads to tremendous economic losses yearly. Currently, there are no approved drugs for the treatment and control of this virus. Our previous studies screened the herb Magnolia officinalis from many traditional Chinese medicines, and we isolated and identified magnolol as its main active compound against multiple rhabdoviruses, including MSRV. On the basis of the structure–activity relationship and pharmacophore model of magnolol, two new magnolol derivatives, namely, hydrogenated magnolol and 2,2′-dimethoxy-magnolol, were designed and synthesized. Their anti-MSRV activities were systematically investigated both in vitro and in vivo. By comparing the half-maximal inhibitory concentration (IC50), it was found that hydrogenated magnolol possessed a higher anti-MSRV activity than magnolol and 2,2′-dimethoxy-magnolol, with an IC50 of 13.37 μM. Furthermore, hydrogenated magnolol exhibited a protective effect on the grass carp ovary (GCO) cell line by reducing the cytopathic effect induced by MSRV. Further studies revealed that hydrogenated magnolol did not directly impact virions or interfere with MSRV adsorption. It worked within the 6–8 h of the phase of virus replication. In vivo treatment of MSRV infection with magnolol and hydrogenated magnolol showed that they significantly improved the survival rate by 44.6% and 62.7%, respectively, compared to MSRV-infected groups. The viral load measured by the expression of viral glycoprotein in the organs including the liver, spleen, and kidney also significantly decreased when fish were intraperitoneally injected at a dose of 20 mg/kg. Altogether, the structural optimization of magnolol via hydrogenation of the propylene groups increased its anti-MSRV activity both in vitro and in vivo. These results may provide a valuable reference for anti-MSRV drug discovery and development in aquaculture.
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