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Open AccessArticle

Structural Basis for Inhibiting Porcine Epidemic Diarrhea Virus Replication with the 3C-Like Protease Inhibitor GC376

by 1,†, 1,†, 1, 1, 1,2,3 and 1,2,*
1
State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
2
Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China
3
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2020, 12(2), 240; https://doi.org/10.3390/v12020240
Received: 23 December 2019 / Revised: 26 January 2020 / Accepted: 31 January 2020 / Published: 21 February 2020
(This article belongs to the Section Animal Viruses)
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. View Full-Text
Keywords: coronavirus; PEDV 3CLpro; inhibitor; crystal structure; complex coronavirus; PEDV 3CLpro; inhibitor; crystal structure; complex
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MDPI and ACS Style

Ye, G.; Wang, X.; Tong, X.; Shi, Y.; Fu, Z.F.; Peng, G. Structural Basis for Inhibiting Porcine Epidemic Diarrhea Virus Replication with the 3C-Like Protease Inhibitor GC376. Viruses 2020, 12, 240. https://doi.org/10.3390/v12020240

AMA Style

Ye G, Wang X, Tong X, Shi Y, Fu ZF, Peng G. Structural Basis for Inhibiting Porcine Epidemic Diarrhea Virus Replication with the 3C-Like Protease Inhibitor GC376. Viruses. 2020; 12(2):240. https://doi.org/10.3390/v12020240

Chicago/Turabian Style

Ye, Gang; Wang, Xiaowei; Tong, Xiaohan; Shi, Yuejun; Fu, Zhen F.; Peng, Guiqing. 2020. "Structural Basis for Inhibiting Porcine Epidemic Diarrhea Virus Replication with the 3C-Like Protease Inhibitor GC376" Viruses 12, no. 2: 240. https://doi.org/10.3390/v12020240

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