Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease
Yue Zhang,
Huijie Chen,
Mengmeng Zou,
Rick Oerlemans,
Changhao Shao,
Yudong Ren,
Ruili Zhang,
Xiaodan Huang,
Guangxing Li,
Yingying Cong
Affiliations
Yue Zhang
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Huijie Chen
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Mengmeng Zou
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Rick Oerlemans
Department of Drug Design, University of Groningen, 9713 AV Groningen, The Netherlands
Changhao Shao
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Yudong Ren
Department of Computer Science and Technology, College of Electrical and Information Technology, Northeast Agricultural University, Harbin 150030, China
Ruili Zhang
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Xiaodan Huang
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Guangxing Li
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
Yingying Cong
Veterinary Pathology Laboratory, College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China
The porcine epidemic diarrhea virus (PEDV) is an Alphacoronavirus (α-CoV) that causes high mortality in infected piglets, resulting in serious economic losses in the farming industry. Hypericin is a dianthrone compound that has been shown as an antiviral activity on several viruses. Here, we first evaluated the antiviral effect of hypericin in PEDV and found the viral replication and egression were significantly reduced with hypericin post-treatment. As hypericin has been shown in SARS-CoV-2 that it is bound to viral 3CLpro, we thus established a molecular docking between hypericin and PEDV 3CLpro using different software and found hypericin bound to 3CLpro through two pockets. These binding pockets were further verified by another docking between hypericin and PEDV 3CLpro pocket mutants, and the fluorescence resonance energy transfer (FRET) assay confirmed that hypericin inhibits the PEDV 3CLpro activity. Moreover, the alignments of α-CoV 3CLpro sequences or crystal structure revealed that the pockets mediating hypericin and PEDV 3CLpro binding were highly conserved, especially in transmissible gastroenteritis virus (TGEV). We then validated the anti-TGEV effect of hypericin through viral replication and egression. Overall, our results push forward that hypericin was for the first time shown to have an inhibitory effect on PEDV and TGEV by targeting 3CLpro, and it deserves further attention as not only a pan-anti-α-CoV compound but potentially also as a compound of other coronaviral infections.
