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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.
Highlights
Porcine epidemic diarrhea virus (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 novelCoronavirus Disease 2019 (COVID-19) [5]
DMSO was used as the negative control
The results indicated that 57 (6.26%) compounds showed no apparent cytotoxicity, and reduced cytopathic effect (CPE) by 50% compared with DMSO alone
Summary
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 novelCoronavirus Disease 2019 (COVID-19) [5]. 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. The latest research indicates that airborne transmission may contribute to a PEDV outbreak [7], similar to SARS-CoV-2 and MERS-CoV. There is a need for alternative approaches to control this disease, such as effective antiviral drugs for PEDV treatment. Several host antiviral factors, including the bone marrow stromal cell antigen 2 (BST2) [9], interleukin-11
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