A panel of janus kinase inhibitors identified with anti-inflammatory effects protect mice from lethal influenza virus infection.

Influenza remains a significant threat to public health. In severe cases, excessive inflammation can lead to severe pneumonia or acute respiratory distress syndrome, contributing to patient morbidity and mortality. While antivirals can be effective if administered early, current anti-inflammatory drugs have limited success in treating severe cases. Therefore, discovering new anti-inflammatory agents to inhibit influenza-related inflammatory diseases is crucial. Herein, we screened a drug library with known targets using a human monocyte U937 infected with the influenza virus to identify novel anti-inflammatory agents. We also evaluated the anti-inflammatory effects of the hit compounds in an influenza mouse model. Our research revealed that JAK inhibitors exhibited a higher hit rate and more potent inhibition effect than inhibitors targeting other drug targets in vitro. Of the 22 JAK inhibitors tested, 15 exhibited robust anti-inflammatory activity against influenza virus infection in vitro. Subsequently, we evaluated the efficacy of 10 JAK inhibitors using an influenza mouse model and observed that seven provided protection ranging from 40% to 70% against lethal influenza virus infection. We selected oclacitinib as a representative compound for an extensive study to further investigate the in vivo therapeutic potential of JAK inhibitors for severe influenza-associated inflammation. Our results revealed that oclacitinib effectively suppressed neutrophil and macrophage infiltration, reduced pro-inflammatory cytokine production, and ultimately mitigated lung injury in mice infected with lethal influenza virus without impacting viral titer. These findings suggest that JAK inhibitors can modulate immune responses to influenza virus infection and may serve as potential treatments for influenza.IMPORTANCEAntivirals exhibit limited efficacy in treating severe influenza when not administered promptly during the infection. Current steroidal and nonsteroidal anti-inflammatory drugs demonstrate restricted effectiveness against severe influenza or are associated with significant side effects. Therefore, there is an urgent need for novel anti-inflammatory agents that possess high potency and minimal adverse reactions. In this study, 15 JAK inhibitors were identified through a screening process based on their anti-inflammatory activity against influenza virus infection in vitro. Remarkably, 7 of the 10 selected inhibitors exhibited protective effects against lethal influenza virus infection in mice, thereby highlighting the potential therapeutic value of JAK inhibitors for treating influenza.

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.

Identification of Inhibitors and Drug Targets for Human Adenovirus Infections.

Adenoviruses can cause infections in people of all ages at all seasons of the year. Adenovirus infections cause mild to severe illnesses. Children, immunocompromised patients, or those with existing respiratory or cardiac disease are at higher risk. Unfortunately, there are no commercial drugs or vaccines available on the market for adenovirus infections. Therefore, there is an urgent need to discover new antiviral drugs or drug targets for adenovirus infections. To identify potential antiviral agents for adenovirus infections, we screened a drug library containing 2138 compounds, most of which are drugs with known targets and past phase I clinical trials. On a cell-based assay, we identified 131 hits that inhibit adenoviruses type 3 and 5. A secondary screen confirmed the antiviral effects of 59 inhibitors that inhibit the replication of adenoviruses type 3 or 5. Most of the inhibitors target heat shock protein, protein tyrosine kinase, the mTOR signaling pathway, and other host factors, suggesting that these host factors may be essential for replicating adenoviruses. Through this study, the newly identified adenovirus inhibitors may provide a start point for developing new antiviral drugs to treat adenovirus infections. Further validation of the identified drug targets can help the development of new therapeutics against adenovirus infections.