Identification of two antiviral inhibitors targeting 3C-like serine/3C-like protease of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine epidemic diarrhea virus (PEDV) are highly virulent and contagious porcine pathogens that cause tremendous economic losses to the swine industry worldwide. Currently, there is no effective treatment for PRRSV and PEDV, and commercial vaccines do not induce sterilizing immunity. In this study, we screened a library of 1000 compounds and identified two specific inhibitors, designated compounds 2 and 3, which target the PRRSV 3C-like serine protease (3CLSP). First, we evaluated the inhibitory effects of compounds 2 and 3 on PRRSV 3CLSP activity. Next, we determined the anti-PRRSV capacity of compounds 2 and 3 in MARC-145 cells and obtained EC and CC values of 57μM (CC=479.9μM) and 56.8μM (CC=482.8μM), respectively. Importantly, compounds 2 and 3 also targeted the PEDV 3C-like protease (3CL protease) and inhibited PEDV replication, showing EC and CC values of 100μM (CC=533.8μM) and 57.9μM (CC=522.3μM), respectively. Finally, our results indicated that the active sites (His39 in 3CLSP and His41 in 3CL protease) were conservative, and contacted compounds 2 and 3 via hydrogen bonds and hydrophobic forces in the putative substrate-binding models. In summary, compounds 2 and 3 exhibit broad-spectrum antiviral activity and may facilitate the development of antiviral drugs against PRRSV and PEDV.

Protective Effect of Zinc Oxide and Its Association with Neutrophil Degranulation in Piglets Infected with Porcine Epidemic Diarrhea Virus

“…PEDV is the main pathogen of lethal watery diarrhea in piglets, and the emergency of highly virulent strains makes classical vaccines unable to provide effective protection against PEDV [ 6 ]. Although a variety of compounds have been studied, the prevention and control of PED are still quite challenging [ 16 , 17 ]. ZnO is a common nutritional enhancer with antibacterial, antidiarrhea and growth-promoting properties [ 9 ].…”

Towards potential inhibitors of COVID-19 main protease Mpro by virtual screening and molecular docking study

“…Over the last two years, important results have been obtained with a new class of antivirals protease inhibitors (PIs) 11 [19,20]. 12 These inhibitors are characterized by significant antiviral activity, having a particular interest in the current therapeutic approach to the treatment of HIV [21] as well as in the treatment of hepatitis C [22,23].…”

Tomatidine inhibits porcine epidemic diarrhea virus replication by targeting 3CL protease

“…It is an FDA-approved compound with molecular weight similar to tomatidine, but it has no antiviral activity on PEDV (according the data from HTS). Tomatidine (25, 50 μM), obacunone (50 μM, negative control) or DMSO were pre-incubated with 1 μM 3CLpro for 20 min at 37 °C, and 10 μM FRET peptide was added to the mixture in a black 96-well plate [ 21 ]. The mixtures were then further incubated at 37 °C for 20 min, and fluorescence was monitored at 340 nm excitation and 485 nm emissions every minute.…”