Verapamil HCl demonstrates antiviral activity against porcine reproductive and respiratory syndrome virus by regulating Ca 2+ influx and promoting type I interferon production

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) poses a major challenge to swine health, impairing reproductive performance and causing respiratory disorders in pigs. Thus, it creates a considerable economic burden for the global pig production industry. Current prevention and control strategies for PRRSV remain largely ineffective, necessitating the development of novel antiviral drugs. In the current study, we examined how Verapamil HCl could potentially protect host cells against PRRSV infection using both cellular and animal models. Further, we explored the molecular mechanisms underlying these potential anti-PRRSV effects. We discovered that Verapamil HCl suppresses PRRSV infection in MARC-145 cells, PK-15 CD163 cells, and porcine alveolar macrophages. Mechanistic analyses revealed that Verapamil HCl inhibits PRRSV-induced calcium influx in susceptible cells. Additionally, we found that Verapamil HCl enhances heme oxygenase-1 production by activating the p38/Nrf2/Keap-1/HO-1 signaling pathway, subsequently triggering antiviral interferon responses. Finally, animal experiments demonstrated that Verapamil HCl administration significantly reduces viral replication and decreases pulmonary damage in piglets. Collectively, these results suggested that Verapamil HCl may serve as a promising new therapeutic option for treating PRRSV infections. IMPORTANCE Verapamil HCl is known to suppress infections caused by several viruses, including respiratory syncytial virus, bovine herpesvirus 1, and SARS-CoV-2. However, the potential anti-PRRSV mechanisms of Verapamil HCl remain unknown. This study demonstrates that Verapamil HCl exerts anti-PRRSV effects by attenuating the Ca 2+ imbalance induced by PRRSV. Furthermore, Verapamil HCl can promote interferon-mediated antiviral responses and reduce pro-inflammatory factor production during PRRSV infection via p38/Nrf2/Keap-1/HO-1 axis activation. These findings indicate that Verapamil HCl could be a very effective treatment agent against PRRSV.