Abstract
Porcine epidemic diarrhea virus (PEDV), being highly virulent and contagious in piglets, has caused significant damage to the pork industries of many countries worldwide. There are no commercial drugs targeting coronaviruses (CoVs), and few studies on anti-PEDV inhibitors. The coronavirus 3C-like protease (3CLpro) has a conserved structure and catalytic mechanism and plays a key role during viral polyprotein processing, thus serving as an appealing antiviral drug target. Here, we report the anti-PEDV effect of the broad-spectrum inhibitor GC376 (targeting 3Cpro or 3CLpro of viruses in the picornavirus-like supercluster). GC376 was highly effective against the PEDV 3CLpro and exerted similar inhibitory effects on two PEDV strains. Furthermore, the structure of the PEDV 3CLpro in complex with GC376 was determined at 1.65 Å. We elucidated structural details and analyzed the differences between GC376 binding with the PEDV 3CLpro and GC376 binding with the transmissible gastroenteritis virus (TGEV) 3CLpro. Finally, we explored the substrate specificity of PEDV 3CLpro at the P2 site and analyzed the effects of Leu group modification in GC376 on inhibiting PEDV infection. This study helps us to understand better the PEDV 3CLpro substrate specificity, providing information on the optimization of GC376 for development as an antiviral therapeutic against coronaviruses.
Highlights
Porcine epidemic diarrhea virus (PEDV), which was first observed in Europe in 1971 [1], belongs to the genus Alphacoronavirus in the family Coronaviridae and causes severe diarrhea, vomiting, dehydration and high mortality in neonatal piglets, resulting in severe agricultural loss [2,3]
1), which was pro with an IC50 of approximately 1.11 μM (Figure 1), which strong inhibitory effects on the comparable to the IC50 values of other coronaviruses reported in a previous study [35]
Several remarkably potent drugs targeting individual viral proteases have been developed against important human pathogens, such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) [45,46,47,48]
Summary
Porcine epidemic diarrhea virus (PEDV), which was first observed in Europe in 1971 [1], belongs to the genus Alphacoronavirus in the family Coronaviridae and causes severe diarrhea, vomiting, dehydration and high mortality in neonatal piglets, resulting in severe agricultural loss [2,3]. Since PEDV was first identified, outbreaks have been reported in many swine-producing countries, notably in Europe and. Before 2010, several commercial vaccines were widely used to control the spread of PEDV in. Since 2010, frequent outbreaks of highly virulent strains of PEDV have occurred in. Asia, and these outbreaks have been severe in China [4,5,6]. The vaccines based on classic strains failed to control infection [2]. A vaccine-resistant PEDV strain emerged in the United States for the first time and spread rapidly throughout the country, causing large economic
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
