Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease
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RESEARCH ARTICLE
Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease Pengcheng Wang1, Juan Bai1, Xuewei Liu1, Mi Wang1, Xianwei Wang1,2* and Ping Jiang1,2*
Abstract Porcine epidemic diarrhea virus (PEDV) causes lethal diarrhea in suckling piglets, leading to severe economic losses worldwide. There is an urgent need to find new therapeutic methods to prevent and control PEDV. Not only is there a shortage of commercial anti-PEDV drugs, but available commercial vaccines fail to protect against highly virulent PEDV variants. We screened an FDA-approved library of 911 natural products and found that tomatidine, a steroidal alkaloid extracted from the skin and leaves of tomatoes, demonstrates significant inhibition of PEDV replication in Vero and IPEC-J2 cells in vitro. Molecular docking and molecular dynamics analysis predicted interactions between tomatidine and the active pocket of PEDV 3CL protease, which were confirmed by fluorescence spectroscopy and isothermal titration calorimetry (ITC). The inhibiting effect of tomatidine on 3CL protease was determined using cleavage visualization and FRET assay. Tomatidine-mediated blocking of 3CL protease activity in PEDV-infected cells was examined by western blot detection of the viral polyprotein in PEDV-infected cells. It indicates that tomatidine inhibits PEDV replication mainly by targeting 3CL protease. In addition, tomatidine also has antiviral activity against transmissible gastroenteritis virus (TGEV), porcine reproductive and respiratory syndrome virus (PRRSV), encephalo myocarditis virus (EMCV) and seneca virus A (SVA) in vitro. These results may be helpful in developing a new prophylactic and therapeutic strategy against PEDV and other swine disease infections. Keywords: tomatidine, PEDV replication, 3CL protease Introduction PEDV, an enveloped, positive-sense, single-stranded RNA virus, is a member of the Coronavirinae subfamily [1, 2], which comprises viruses that cause a variety of diseases in mammals and birds, ranging from enteritis in cows and pigs, to upper respiratory disease in chickens, and potentially lethal human respiratory infections, such as severe acute respiratory syndrome (SARS) [3], Middle East respiratory syndrome (MERS) [4], and the novel *Correspondence: [email protected]; [email protected] 1 Key Laboratory of Animal Disease Diagnostics and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China Full list of author information is available at the end of the article
Coronavirus Disease 2019 (COVID-19) [5]. Fecal–oral transmission is believed to be the main mode of PEDV transmission [6]. The latest research indicates that airborne transmission may also contribute to a PEDV outbreak [7], similar to SARS-CoV-2 and MERS-CoV. Owing to antigenic, genetic (> 10% amino acid variation between respective S-proteins) and phylogenetic (G1 vs G
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