Background
Type: Article

Immunomodulatory effects of a rationally designed peptide mimetic of human IFNβ in EAE model of multiple sclerosis

Journal: Progress in Neuro-Psychopharmacology and Biological Psychiatry (18784216)Year: 2 March 2018Volume: 82Issue: Pages: 49 - 61
Poorebrahim M. Asghari M. Abazari M.F. Askari H. Sadeghi S.Taheri Kafrani A.a Nasr-Esfahani M.H. Ghoraeian P. Aleagha M.N. Arab S.S.
GreenDOI:10.1016/j.pnpbp.2017.11.028Language: English

Abstract

The efficiency of interferon beta (IFNβ)-based drugs is considerably limited due to their undesirable properties, especially high immunogenicity. In this study, for the first time we investigated the impact of a computationally designed peptide mimetic of IFNβ called MSPEP27, in the animal model of MS. A peptide library was constructed using the Rosetta program based on the predominant IFNAR1-binding site of IFNβ. Molecular docking studies were carried out using ClusPro and HADDOCK tools. The GROMACS package was subsequently used for molecular dynamics (MD) simulations. Validation of peptide-receptor interaction was carried out using intrinsic fluorescence measurements. To explore in silico findings further, experimental autoimmune encephalomyelitis (EAE) was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55). Mice were then separated into distinct groups and intravenously received 10 or 20 mg kg− 1 of MSPEP27 or IFNβ. The inflammatory mediators were monitored by immunohistochemistry (IL17, CD11b, CD45), quantitative real-time PCR (MMP2, MMP9, TIMP-1) and enzyme-linked immunosorbent assay (IL1β TNFα) methods. Among the library of tolerated peptides, MSPEP27, a peptide with favorable physicochemical properties, was chosen for further experiments. This peptide was shown to significantly interact with IFNAR1 in a dose-dependent manner. Like IFNβ MSPEP27 could efficiently bind to IFNAR1 and form a stable peptide-receptor complex during 30 ns MD simulations. In vivo analyses revealed that MSPEP27 could lessen inflammation by modulating the levels of inflammatory mediators. According to our results, MSPEP27 peptide could efficiently bind to IFNAR1 and suppress neuroinflammation in vivo. We conclude that MSPEP27 has protective effects against MOG-induced EAE via reduction of immune dysfunction and inflammation. © 2017 Elsevier Inc.


Author Keywords

EAEIFNβInflammationMSPEP27Multiple sclerosisPeptide

Other Keywords

AnimalsCerebral CortexEncephalomyelitis, Autoimmune, ExperimentalGene ExpressionHumansImmunomodulationInterferon-betaMaleMice, Inbred C57BLMolecular Docking SimulationMolecular Dynamics SimulationReceptor, Interferon alpha-betabeta interferonCD11b antigengelatinase Agelatinase Binterferon receptorinterleukin 1betamyelin oligodendrocyte glycoproteinpeptidereceptor type tyrosine protein phosphatase Ctissue inhibitor of metalloproteinase 1tumor necrosis factoralpha beta interferon receptoranimal cellanimal experimentanimal modelanimal tissueantiinflammatory activityArticlebinding sitebiomimeticscomputer modelcontrolled studydrug receptor bindingenzyme linked immunosorbent assayexperimental neuroinflammationfluorescence analysishumanhuman cellimmunohistochemistryin vivo studyMOG-induced experimental autoimmune encephalomyelitismolecular dockingmolecular dynamicsmousemultiple sclerosisneuroprotectionnonhumanpeptide libraryphysical chemistryprotein interactionprotein protein interactionreal time polymerase chain reactionanimalbrain cortexC57BL mouseexperimental autoimmune encephalomyelitisimmunologymetabolism