PA-824 inhibits porcine epidemic diarrhea virus infection <i>in vivo</i> and <i>in vitro</i> by inhibiting p53 activation

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) is a type A coronavirus that causes severe watery diarrhea in piglets, resulting in severe economic losses worldwide. Therefore, new approaches to control PEDV infection are essential for a robust and sustainable pig industry. We screened 314 small-molecule drug libraries provided by Selleck and found that four drugs had obviously inhibitory effects on PEDV in Vero cells. PA-824, which had the highest SI index and the most reliable clinical safety, was selected for in vivo experiments. Animal attack tests showed that PA-824 effectively alleviated the clinical signs, intestinal pathological changes, and inflammatory responses in lactating piglets after PEDV infection. To further investigate the antiviral mechanism of PA-824, we measured the inhibitory effect of PA-824 on PEDV proliferation in a dose-dependent manner. By exploring the effect of PA-824 on the PEDV life cycle, we found that PA-824 acted directly on viral particles and hindered the adsorption, internalization, and replication phases of the virus, followed by molecular docking analysis to predict the interaction between PA-824 and PEDV non-structural proteins. Finally, we found that PA-824 could inhibit the apoptotic signaling pathway by suppressing PEDV-induced p53 activation. These results suggest that PA-824 could be protective against PEDV infection in piglets and could be developed as a drug or a feed additive to prevent and control PEDV diseases.

IMPORTANCE

PEDV is a highly contagious enteric coronavirus that widely spread worldwide, causing serious economic losses. There is no drug or vaccine to effectively control PEDV. In this study, we found that PA-824, a compound of mycobacteria causing pulmonary diseases, inhibited PEDV proliferation in both in vitro and in vivo

. We also found that PA-824 directly acted on viral particles and hindered the adsorption, internalization, and replication stages of the virus. In addition, we found that PA-824 could inhibit the apoptotic signaling pathway by inhibiting PEDV-induced p53 activation. In conclusion, it is expected to be developed as a drug or a feed additive to prevent and control PEDV diseases.

Background:

Porcine epidemic diarrhea virus (PEDV) is a type A coronavirus that causes severe watery diarrhea in piglets, resulting in severe economic losses worldwide. Therefore, new approaches to control PEDV infection are essential for a robust and sustainable pig industry. PEDV is a highly contagious enteric coronavirus that widely spread worldwide, causing serious economic losses. There is no drug or vaccine to effectively control PEDV.

Methods:

We screened 314 small-molecule drug libraries provided by Selleck and found that four drugs had obviously inhibitory effects on PEDV in Vero cells. PA-824, which had the highest SI index and the most reliable clinical safety, was selected for in vivo experiments. Animal attack tests showed that PA-824 effectively alleviated the clinical signs, intestinal pathological changes, and inflammatory responses in lactating piglets after PEDV infection. To further investigate the antiviral mechanism of PA-824, we measured the inhibitory effect of PA-824 on PEDV proliferation in a dose-dependent manner. By exploring the effect of PA-824 on the PEDV life cycle, we found that PA-824 acted directly on viral particles and hindered the adsorption, internalization, and replication phases of the virus, followed by molecular docking analysis to predict the interaction between PA-824 and PEDV non-structural proteins. Finally, we found that PA-824 could inhibit the apoptotic signaling pathway by suppressing PEDV-induced p53 activation.

Results:

PA-824 effectively alleviated the clinical signs, intestinal pathological changes, and inflammatory responses in lactating piglets after PEDV infection. PA-824 inhibited PEDV proliferation in a dose-dependent manner. PA-824 acted directly on viral particles and hindered the adsorption, internalization, and replication phases of the virus. PA-824 could inhibit the apoptotic signaling pathway by suppressing PEDV-induced p53 activation.

Data Summary:

Four drugs had obviously inhibitory effects on PEDV in Vero cells. PA-824 had the highest SI index. PA-824 inhibited PEDV proliferation in a dose-dependent manner.

Conclusions:

These results suggest that PA-824 could be protective against PEDV infection in piglets and could be developed as a drug or a feed additive to prevent and control PEDV diseases. It is expected to be developed as a drug or a feed additive to prevent and control PEDV diseases.

Practical Significance:

PA-824 could be developed as a drug or a feed additive to prevent and control PEDV diseases, providing new approaches essential for a robust and sustainable pig industry.