口蹄疫病毒(FMDV)属于Picornaviridae家族,是影响偶蹄家畜的重要病原体。然而,目前既没有涵盖所有血清型的有效疫苗,也没有针对FMDV感染的特异性抗病毒药物.在这项研究中,我们采用虚拟筛选来筛选针对RNA依赖性RNA聚合酶(RdRp)的次级代谢物萜类化合物,或者3Dpol,FMDV。随后,我们确定了32种排名最高的萜类化合物的潜在抗病毒活性,揭示了大陆酸,脱氢松香酸(松香二萜),Brusatol,咖啡因D,和BruceineE(四环三萜类)显着降低了类萜治疗的细胞病变效应和病毒感染,FMDV以剂量依赖性方式感染BHK-21细胞,纳摩尔到低微摩尔水平。FMDV小基因组分析表明,布鲁沙醇和布鲁咖啡因D,特别是,有效阻止FMDV3Dpol活动,表现出IC50值在0.37-0.39µM的范围内,超过了抗病毒药物控制的功效,利巴韦林.Continentalic酸和BruceineE对FMDV3Dpol具有中等抑制作用。预测的蛋白质-配体相互作用证实了这些潜在的萜类化合物与FMDV3Dpol的主要催化和旁观者残基相互作用。此外,当与利巴韦林联合使用时,布沙妥和布丁D表现出累加效应。总之,来自自然资源的萜类化合物有望开发抗FMD药物。
Foot-and-mouth disease virus (FMDV) belongs to the Picornaviridae family and is an important pathogen affecting cloven-hoof livestock. However, neither effective vaccines covering all serotypes nor specific antivirals against FMDV infections are currently available. In this study, we employed virtual screening to screen for secondary metabolite terpenoids targeting the RNA-dependent RNA polymerase (RdRp), or 3Dpol, of FMDV. Subsequently, we identified the potential antiviral activity of the 32 top-ranked terpenoids, revealing that continentalic acid, dehydroabietic acid (abietic diterpenoids), brusatol, bruceine D, and bruceine E (tetracyclic triterpenoids) significantly reduced cytopathic effects and viral infection in the terpenoid-treated, FMDV-infected BHK-21 cells in a dose-dependent manner, with nanomolar to low micromolar levels. The FMDV minigenome assay demonstrated that brusatol and bruceine D, in particular, effectively blocked FMDV 3Dpol activity, exhibiting IC50 values in the range of 0.37-0.39 µM and surpassing the efficacy of the antiviral drug control, ribavirin. Continentalic acid and bruceine E exhibited moderate inhibition of FMDV 3Dpol. The predicted protein-ligand interaction confirmed that these potential terpenoids interacted with the main catalytic and bystander residues of FMDV 3Dpol. Additionally, brusatol and bruceine D exhibited additive effects when combined with ribavirin. In conclusion, terpenoids from natural resources show promise for the development of anti-FMD agents.