Abstract
Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease, which has been continuously prevalent in Asia in recent years. In children, severe cases can lead to death, and no prophylactic or therapeutic measures against EV71 infection are available. The 3C proteases of EV71 play an important role in viral replication and are an ideal drug target. In previous work, we resolved the crystal structure for EV71 3Cpro. In this report, we took advantage of the automated docking program AutoDock 4.0 to simulate EV71 3Cpro-ligand conformation. 7-hydroxyflavone (HF) and its phosphate ester(FIP) were predicted to bind with EV71 3Cpro.In an in vitro protease inhibition assay, FIP inhibited EV71 3Cpro protease activity. Both flavones were highly active against EV71, protecting cells from EV71 infection. Replication of viral RNA and formation of EV71 plaque were all strongly inhibited in cells. These results indicated that HF and FIP may serve as potential protective agents in the treatment of patients with chronic EV71 infection.
Highlights
Hand-foot-and-mouth disease (HFMD) is a common viral illness of infants and children that causes fever, sore throat, blisters, and skin rash for which there is no clinically effective therapy
We demonstrated that Enterovirus 71 (EV71) 3Cpro can inhibit cellular antiviral responses of the infected cell by disruptions of the retinoic acid-inducible gene I, Toll-like receptor 3, and interferon regulatory factor 7 signaling pathways [15,16,17]
We found that 7-hydroxyflavone (HF) from the flavone subgroup of flavonoids can be stably inserted into the pocket of EV71 3Cpro
Summary
Hand-foot-and-mouth disease (HFMD) is a common viral illness of infants and children that causes fever, sore throat, blisters, and skin rash for which there is no clinically effective therapy. EV71 has been implicated in an increasing number of outbreaks throughout the world and is classified as an emerging infectious disease with pandemic potential [3,4,5]. This virus is classified as a member of the enterovirus species A within the genus Enterovirus of the Picornaviridae family. It has a ,7.4 kb positive-sense, single-stranded RNA genome with a single open reading frame encoding a polyprotein flanked by 59- and 39untranslated regions. The non-structural proteins are found in the P2 and P3 regions
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