Abstract
Enterovirus 71 (EV-A71) is one of the predominant etiological agents of hand, foot and mouth disease (HMFD), which can cause severe central nervous system infections in young children. There is no clinically approved vaccine or antiviral agent against HFMD. The SP40 peptide, derived from the VP1 capsid of EV-A71, was reported to be a promising antiviral peptide that targeted the host receptor(s) involved in viral attachment or entry. So far, the mechanism of action of SP40 peptide is unknown. In this study, interactions between ten reported cell receptors of EV-A71 and the antiviral SP40 peptide were evaluated through molecular docking simulations, followed by in vitro receptor blocking with specific antibodies. The preferable binding region of each receptor to SP40 was predicted by global docking using HPEPDOCK and the cell receptor-SP40 peptide complexes were refined using FlexPepDock. Local molecular docking using GOLD (Genetic Optimization for Ligand Docking) showed that the SP40 peptide had the highest binding score to nucleolin followed by annexin A2, SCARB2 and human tryptophanyl-tRNA synthetase. The average GoldScore for 5 top-scoring models of human cyclophilin, fibronectin, human galectin, DC-SIGN and vimentin were almost similar. Analysis of the nucleolin-SP40 peptide complex showed that SP40 peptide binds to the RNA binding domains (RBDs) of nucleolin. Furthermore, receptor blocking by specific monoclonal antibody was performed for seven cell receptors of EV-A71 and the results showed that the blocking of nucleolin by anti-nucleolin alone conferred a 93% reduction in viral infectivity. Maximum viral inhibition (99.5%) occurred when SCARB2 was concurrently blocked with anti-SCARB2 and the SP40 peptide. This is the first report to reveal the mechanism of action of SP40 peptide in silico through molecular docking analysis. This study provides information on the possible binding site of SP40 peptide to EV-A71 cellular receptors. Such information could be useful to further validate the interaction of the SP40 peptide with nucleolin by site-directed mutagenesis of the nucleolin binding site.
Highlights
Enterovirus 71 (EV-A71) belongs to the Enterovirus A species of the Picornaviridae family and is known to cause hand, foot and mouth disease (HMFD)
This study aims to determine the interaction site of the RD cells receptor(s) with SP40 peptide by in silico study through molecular docking analysis, followed by receptor blocking using specific antibodies for selected receptors
Our observations indicated that antibody treatments to block specific receptors of EV-A71 did show a reduction in infectivity such as treatment with anti-SCARB2 resulted in 49% residual infectivity but could not completely abolish infectivity
Summary
Enterovirus 71 (EV-A71) belongs to the Enterovirus A species of the Picornaviridae family and is known to cause hand, foot and mouth disease (HMFD). It poses significant health risks to young children under 5 years of age and the infection has been reported in older children and adults [1]. There were significant morbidity and mortality in HFMD outbreaks from Taiwan and China [3,4,5]. HFMD is generally a mild and self-limiting disease characterized by fever, rashes on the hands and feet, and mouth ulcers. Complications of HFMD infections include aseptic meningitis, brainstem encephalitis, acute flaccid paralysis and pulmonary edema which could lead to death [1,6,7]. In 2017, almost two million cases of HFMD, including 96 deaths, were recorded in China. Less than a year later, in July 2018, 1,381,685 cases of HFMD were reported, including 26 fatal cases [8]. The major pathogens involved in the majority of HFMD outbreaks were EV-A71 and CV-A16, but recent studies showed that, besides these two pathogens, other enteroviruses, such as CV-A6 and CV-A10, have emerged as significant pathogens from recent HFMD outbreaks [9,10,11]
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