Sodium Polyoxotungstate Inhibits the Replication of Influenza Virus by Blocking the Nuclear Import of vRNP.

Both pandemic and seasonal influenza are major health concerns, causing significant mortality and morbidity. Current influenza drugs primarily target viral neuraminidase and RNA polymerase, which are prone to drug resistance. Polyoxometalates (POMs) are metal cation clusters bridged by oxide anions. They have exhibited potent anti-tumor, antiviral, and antibacterial effects. They have remarkable activity against various DNA and RNA viruses, including human immunodeficiency virus, herpes simplex virus, hepatitis B and C viruses, dengue virus, and influenza virus. In this study, we have identified sodium polyoxotungstate (POM-1) from an ion channel inhibitor library. In vitro, POM-1 has been demonstrated to have potent antiviral activity against H1N1, H3N2, and oseltamivir-resistant H1N1 strains. POM-1 can cause virion aggregation during adsorption, as well as endocytosis. However, the aggregation is reversible; it does not interfere with virus adsorption and endocytosis. Our results suggest that POM-1 exerts its antiviral activity by inhibiting the nuclear import of viral ribonucleoprotein (vRNP). This distinct mechanism of action, combined with its wide range of efficacy, positions POM-1 as a promising therapeutic candidate for influenza treatment and warrants further investigation.

BMS-265246, a Cyclin-Dependent Kinase Inhibitor, Inhibits the Infection of Herpes Simplex Virus Type 1.

Herpes simplex virus type 1 (HSV-1) infections are prevalent illnesses that can cause mucocutaneous ulcerative disease, keratitis, and genital herpes. In patients with compromised immune systems, the infection can lead to serious problems, such as encephalitis. Additionally, neonatal infections can cause brain problems and even death. Current first-line antiviral drugs are nucleoside analog inhibitors that target viral polymerase, and resistant strains have emerged. As a result, new drugs with distinct action modes are needed. Recent research indicates that cyclin-dependent kinases (CDKs) are prospective antiviral targets. Thus, CDK inhibitors may be effective antiviral agents against HSV-1 infection. In this study, we examined a panel of CDK inhibitors that target CDKs in the present study. BMS-265246 (BMS), a CDK 1/2 inhibitor, was found to effectively limit HSV-1 multiplication in Vero, HepG2, and Hela cells. A mechanism of action study suggested that BMS inhibits the early stages of viral replication when added early in the viral infection. The suppression of multiple steps in viral replication by BMS was revealed when HSV-1 infected cells were treated at different time periods in the viral life cycle. Our results suggest that BMS is a potent anti-HSV-1 agent and unique in that it may interfere with multiple steps in HSV-1 replication.

Effect of Drying Kinetics, Volatile Components, Flavor Changes and Final Quality Attributes of Moslae herba during the Hot Air Thin-Layer Drying Process.

Moslae herba is considered to be a functional food ingredient or nutraceutical due to its rich bioactive components. The present research was carried out to investigate the effects of different temperatures (40 °C, 50 °C and 60 °C) on the drying characteristics, textural properties, bioactive compounds, flavor changes and final quality attributes of Moslae herba during the hot air-drying process. The results showed that the Midilli model could effectively simulate the drying process of Moslae herba. The effective moisture diffusivity ranged from 3.14 × 10-5 m2/s to 7.39 × 10-5 m2/s, and the activation energy was estimated to be 37.29 kJ/mol. Additionally, scanning electron microscopy (SEM) images of Moslae herba samples showed the shrinkage of the underlying epidermal layers and glandular trichomes. In total, 23 volatile compounds were detected in Moslae herba. Among them, the content of thymol increased from 28.29% in fresh samples to 56.75%, 55.86% and 55.62% in samples dried at temperatures of 40 °C, 50 °C and 60 °C, respectively, while the other two components, p-cymene and γ-terpinene, decreased with an increase in the temperature. Furthermore, both radar fingerprinting and principal component analysis (PCA) of the electronic nose (E-nose) showed that the flavor substances significantly altered during the drying process. Eventually, drying Moslae herba at 60 °C positively affected the retention of total phenolics, total flavonoids and the antioxidant capacity as compared with drying at 40 °C and 50 °C. The overall results elucidated that drying Moslae herba at the temperature of 60 °C efficiently enhanced the final quality by significantly reducing the drying time and maintaining the bioactive compounds.

Andrographolide and Its Derivative Potassium Dehydrographolide Succinate Suppress PRRSV Replication in Primary and Established Cells via Differential Mechanisms of Action.

Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause significant economic loss worldwide and remains a serious threat to the pork industry. Currently, vaccination strategies provide limited protection against PRRSV infection, and consequently, new antiviral strategies are urgently required. Andrographolide (Andro) and its derivative potassium dehydrographolide succinate (PDS) have been used clinically in China and other Asian countries as therapies for inflammation-related diseases, including bacterial and viral infections, for decades. Here, we demonstrate that Andro and PDS exhibit robust activity against PRRSV replication in Marc-145 cells and primary porcine alveolar macrophages (PAMs). The two compounds exhibited broad-spectrum inhibitory activities in vitro against clinically circulating type 2 PRRSV GD-HD, XH-GD, and NADC30-like HNhx strains in China. The EC50 values of Andro against three tested PRRSV strain infections in Marc-145 cells ranged from 11.7 to 15.3 µmol/L, with selectivity indexes ranging from 8.3 to 10.8, while the EC50 values of PDS ranged from 57.1 to 85.4 µmol/L, with selectivity indexes ranging from 344 to 515. Mechanistically, the anti-PRRSV activity of the two compounds is closely associated with their potent suppression on NF-κB activation and enhanced oxidative stress induced by PRRSV infection. Further mechanistic investigations revealed that PDS, but not Andro, is able to directly interact with PRRSV particles. Taken together, our findings suggest that Andro and PDS are promising PRRSV inhibitors in vitro and deserves further in vivo studies in swine.

Ursolic acid derivatives are potent inhibitors against porcine reproductive and respiratory syndrome virus.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating viral pathogens of swine and has a substantial economic impact on the global pork industry. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Therefore, there is an urgent need to develop new antiviral strategies to prevent PRRSV pandemics. In this study, we showed that 3-O-ß-chacotriosyl ursolic acid (1) and its ester analogs possessed anti-PRRSV activity in vitro, of which bioisosteric surrogates 7-15 were further generated with the aim of enhancing the selective index. Our results showed that amidation of the 17-COOH group of UA could significantly reduce cytotoxicity and enhance anti-PRRSV activity in MARC-145 cells. Among them, compound 9 displayed the strongest anti-PRRSV activity with the least cytotoxicity. Potent inhibition of representative compounds 9 and 12 on PRRSV infection was observed not only in MARC-145 cells, but also in primary porcine alveolar macrophages, PRRSV-target cells in vivo. Furthermore, compounds 8, 9, 12 and 14 exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV NADC30-like and GD-XH strains as well as classical CH-1a and VR2332 strains. Mechanistically, compounds 9 and 12 inhibited PRRSV replication by directly inactivating virions and therefore affecting all tested stages of the virus life cycle, including viral entry, replication and progeny virus release, but did not affect cellular susceptibility to PRRSV. Our findings suggest that compound 9 could be a hit PRRSV inhibitor and deserves further in vivo studies in swine.