Zanthoxylum acanthopodium DC. is a widely used traditional medicinal plant to treat fever, flu, stomachache, traumatic injury, and mosquito bite in tropical and subtropical Asia. This study aimed to investigate the antifungal, anti-inflammatory, antiviral, and larvicidal activities of its fruit essential oil. The essential oil sample from China (EOZC) was mainly composed of limonene (29.78%) and β-myrcene (26.65%), while the sample from Myanmar (EOZM) was dominated by Terpinen-4-ol (43.35%). Both essential oils showed antifungal activity, with 90% minimum inhibitory concentration (MIC₉₀) values ranging from 26.3 to 499 μg/mL. By obviously inhibiting nitric oxide (NO) in RAW 264.7 cells, EOZC (IC₅₀, 16 μg/mL) showed comparable anti-inflammatory activity to the positive control L-NMMA (IC₅₀, 12.2 μg/mL). EOZM showed significant antiviral activity against the dengue virus with an IC₅₀ value of 13 μg/mL. Additionally, both EOZC and EOZM demonstrated dose-dependent larvicidal activity against Aedes albopictus, with LC₅₀ and LC₉₀ values ranging from 45.8 to 144.0 μg/mL. Our results contribute a theoretical foundation for the further application of Zanthoxylum acanthopodium DC. as an antifungal and anti-inflammatory ingredient in the pharmaceutical industry and further indicate that it has the potential to be developed as a new source of natural and eco-friendly medicine for the prevention and treatment of dengue virus.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus that causes the severe fever thrombocytopenia syndrome, which manifests as fever and haemorrhage, accompanied by severe neurological complications. To date, no specific antiviral drugs have been approved for this indication. Herein, we investigated whether vitamin D derivatives inhibit SFTSV both in vitro and in vivo. An in vitro study demonstrated that vitamin D derivatives significantly suppressed viral RNA replication, plaque formation, and protein expression in a dose-dependent manner. Subsequently, in vivo studies revealed that doxercalciferol and alfacalcidol were associated with increased survival and reduced viral RNA load in the blood. Time-of-addition assay suggested that vitamin D derivatives primarily acted during the post-entry phase of SFTSV infection. However, cytopathic effect protective activity was not observed in RIG-I immunodeficient cell line Huh7.5, and the administration of vitamin D derivatives did not improve the survival rates or reduce the blood viral loads in adult A129 mice. Further transcriptome exploration into the antiviral mechanism revealed that alfacalcidol stimulates host innate immunity to exert antiviral effects. To expand the application of vitamin D derivatives, in vitro and in vivo drug combination assays were performed, which highlighted the synergistic effects of vitamin D derivatives and T-705 on SFTSV. The combination of alfacalcidol and T-705 significantly enhanced the therapeutic effects in mice. This study highlights the potential of vitamin D derivatives against SFTSV and suggests that they may have synergistic effects with other compounds used in the treatment of SFTSV infection.

Severe fever with thrombocytopenia syndrome virus (SFTSV), also known as the Dabie Banda virus, is an emerging tick-borne Bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS). Currently, symptomatic treatment and antiviral therapy with ribavirin and favipiravir are used in clinical management. However, their therapeutical efficacy is hardly satisfactory in patients with high viral load. In this study, we explored the antiviral effects of selective estrogen receptor modulators (SERMs) on SFTSV infection and the antiviral mechanisms of a representative SERM, bazedoxifene acetate (BZA). Our data show that SERMs potently inhibited SFTSV-induced cytopathic effect (CPE), the proliferation of infectious viral particles, and viral RNA replication and that BZA effectively protected mice from lethal viral challenge. The mode of action analysis reveals that BZA exerts antiviral effects during the post-entry stage of SFTSV infection. The transcriptome analysis reveals that GRASLND and CYP1A1 were upregulated, while TMEM45B and TXNIP were downregulated. Our findings suggest that SERMs have the potential to be used in the treatment of SFTSV infection.

Seasonal outbreaks and occasional pandemics triggered by influenza viruses annually impose considerable burdens on public health and finances. The continual evolution of viral strains with drug resistance emphasizes the urgency of discovering novel agents for influenza viruses. This study investigated a set of innovative substances derived from Morinda officinalis with antiviral potential against influenza virus strains. The top candidate, anthraquinone-2-carboxylic acid (A2CA), presented antiviral activity against diverse influenza virus strains, including those resistant to oseltamivir. In an influenza mouse model, the pre-administration of A2CA dose-dependently ameliorated influenza A virus (IAV)-mediated weight loss as well as protected mice from a lethal IAV infection. In addition, lung injury and cytokine dysregulation were mitigated. Further investigation revealed that IAV-induced activation of the RIG-I/STAT1 signaling pathway did not occur after A2CA treatment. A time-of-addition assay revealed that A2CA targeted the final phase of intracellular replication, which was further determined by molecular docking between A2CA and the IAV RdRp protein. Finally, transcriptome analysis revealed that the TP53TG3C, CFAP57 and SNX30-DT genes may be involved in the antiviral effects of A2CA. These results play a part in achieving a thorough comprehension of the capacity of A2CA to inhibit influenza virus infection.

SummaryInfluenza virus remains one of the major public health concerns, as it causes annual seasonal epidemics and occasional worldwide pandemics. Vaccines and antiviral drugs are two commonly used countermeasures against influenza virus infection. However, vaccine efficacy is substantially diminished due to antigenic drift and evolution of virus strains, while the clinical application of approved antivirus drugs is increasingly restricted by emerging drug resistance and side effects. Therefore, there is an urgent need for novel anti-influenza drug candidates to treat influenza infections. In this study, we reported that MK-28 effectively inhibits the influenza virus and other RNA viruses in vitro. Our data showed that MK-28 could significantly inhibit viral RNA replication, reduce the production of infectious viral particles, and suppress the synthesis of viral proteins. In vivo administration of MK-28 prolonged the survival of the infected mice, reduced viral loads, and alleviated pathological lesions in lung tissue. The time-of-addition assay and replicon assay suggested that MK-28 acts at the viral replication stage. Further mechanism investigations revealed that MK-28 exerts antiviral activity by activating the protein kinase R-like endoplasmic reticulum kinase (PERK). These findings indicate that MK-28 may represent a promising broad-spectrum drug candidate for combating influenza and other respiratory virus infections.

Enterovirus A71 (EV-A71) is a major causative agent of hand, foot, and mouth disease (HFMD) with neurotropism, and currently no approved antiviral therapies are available. In this study, we found that the ondansetron exhibits antiviral activity against EV-A71 infection. Ondansetron significantly reducing viral RNA levels, progeny virus production, and VP1 protein expression in a dose-dependent manner. In vivo, ondansetron treatment increased survival of neonatal mice and decreased viral loads in multiple tissues. Mechanistically, ondansetron modulates cholesterol metabolism-related genes to affect cell cholesterol stability and interferes with viral attachment during the early stage of infection, thereby inhibiting EV-A71 infection. These findings indicate that ondansetron is a promising candidate for drug repurposing to treat EV-A71 infection.