Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)

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 cap...

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Autores principales:	Malihe Masomian, Salima Lalani, Chit Laa Poh
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	hand, foot and mouth disease molecular docking receptor blocking nucleolin SCARB2 annexin2 Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/7657b214b7704ff38c06fe25c854c518
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spelling	oai:doaj.org-article:7657b214b7704ff38c06fe25c854c5182021-11-11T18:33:31ZMolecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)10.3390/molecules262165761420-3049https://doaj.org/article/7657b214b7704ff38c06fe25c854c5182021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6576https://doaj.org/toc/1420-3049Enterovirus 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.Malihe MasomianSalima LalaniChit Laa PohMDPI AGarticlehand, foot and mouth diseasemolecular dockingreceptor blockingnucleolinSCARB2annexin2Organic chemistryQD241-441ENMolecules, Vol 26, Iss 6576, p 6576 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hand, foot and mouth disease molecular docking receptor blocking nucleolin SCARB2 annexin2 Organic chemistry QD241-441
spellingShingle	hand, foot and mouth disease molecular docking receptor blocking nucleolin SCARB2 annexin2 Organic chemistry QD241-441 Malihe Masomian Salima Lalani Chit Laa Poh Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)
description	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.
format	article
author	Malihe Masomian Salima Lalani Chit Laa Poh
author_facet	Malihe Masomian Salima Lalani Chit Laa Poh
author_sort	Malihe Masomian
title	Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)
title_short	Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)
title_full	Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)
title_fullStr	Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)
title_full_unstemmed	Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)
title_sort	molecular docking of sp40 peptide towards cellular receptors for enterovirus 71 (ev-a71)
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7657b214b7704ff38c06fe25c854c518
work_keys_str_mv	AT malihemasomian moleculardockingofsp40peptidetowardscellularreceptorsforenterovirus71eva71 AT salimalalani moleculardockingofsp40peptidetowardscellularreceptorsforenterovirus71eva71 AT chitlaapoh moleculardockingofsp40peptidetowardscellularreceptorsforenterovirus71eva71
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Molecular Docking of SP40 Peptide towards Cellular Receptors for Enterovirus 71 (EV-A71)

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