Repurposing Axl Kinase Inhibitors for the Treatment of Respiratory Syncytial Virus Infection

by Selleckchem | Jul 02 2023

Respiratory syncytial virus (RSV) infection persists as a common pathogen of pulmonary infection in infants and in the elderly with high morbidity and mortality. However, no specific therapeutics are available. Axl, a member of the TAM (Tyro3, Axl, and Mertk) family receptor kinases, is a pleiotropic inhibitor of the innate immune response and functions as a negative regulator of interferon pathway activation. In this report, we investigated Axl inhibitors for their effects against RSV infection. Axl inhibition with kinase inhibitors, including BMS-777607, R428, and TP-0903, or Axl ablation resulted in a significant reduction of RSV infection in cell-based assays. In an animal model of pulmonary RSV infection, treatment with BMS-777607, R428, or TP-0903 ameliorated pulmonary pathology with a significant reduction of RSV titers in the lung tissues and, consequently, decreased the expression of proinflammatory genes. The host promotes ISG expression for the antiviral response and for viral clearance. We found that Axl inhibition led to more robust IFN-β expression and antiviral gene induction. Thus, the results of this study imply that Axl kinase inhibitors may possess a broad spectrum of antiviral effects by promoting ISG expression.

Comments:

The report you provided describes the investigation of Axl kinase inhibitors as potential therapeutics against respiratory syncytial virus (RSV) infection. RSV is known to cause pulmonary infections in infants and the elderly, leading to significant morbidity and mortality. Currently, there are no specific therapeutics available for RSV infection.

Axl is a member of the TAM family receptor kinases and acts as a negative regulator of the innate immune response, particularly the interferon pathway activation. The study aimed to evaluate the effects of Axl inhibitors on RSV infection.

The researchers tested several Axl kinase inhibitors, including BMS-777607, R428, and TP-0903, in cell-based assays and found that inhibiting Axl or ablating Axl expression resulted in a significant reduction of RSV infection. This suggests that Axl plays a role in promoting RSV infection.

Furthermore, in an animal model of pulmonary RSV infection, treatment with BMS-777607, R428, or TP-0903 showed positive effects. The inhibitors ameliorated pulmonary pathology, reduced RSV titers in lung tissues, and decreased the expression of proinflammatory genes. This indicates that Axl inhibitors have the potential to mitigate RSV-associated lung damage and inflammation.

Interestingly, Axl inhibition also led to increased expression of interferon-beta (IFN-β) and induction of antiviral genes known as interferon-stimulated genes (ISGs). This suggests that Axl inhibitors may enhance the host's antiviral response by promoting the expression of ISGs, which play a crucial role in antiviral defense and viral clearance.

Overall, the study suggests that Axl kinase inhibitors have broad-spectrum antiviral effects against RSV infection by reducing viral replication, ameliorating lung pathology, and promoting the expression of ISGs. These findings provide valuable insights into the potential development of targeted therapeutics for RSV infection, which currently lacks specific treatment options.