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  • Immunomodulatory effects of a rationally designed peptide mimetic of human IFN? in EAE model of multiple sclerosis

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    KennedyPUB5172.pdf (1.444Mb)
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    Accepted Manuscript (AM)
    Author(s)
    Poorebrahim, Mansour
    Asghari, Matin
    Abazari, Mohammad Foad
    Askari, Hassan
    Sadeghi, Solmaz
    Taheri-Kafrani, Asghar
    Nasr-Esfahani, Mohammad Hossein
    Ghoraeian, Pegah
    Aleagha, Maryam Nouri
    Arab, Seyed Shahriar
    Kennedy, Derek
    Montaseri, Alireza
    Mehranfar, Mahsa
    Sanadgol, Nima
    Griffith University Author(s)
    Kennedy, Derek D.
    Year published
    2018
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    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 ...
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    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.
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    Journal Title
    Progress in Neuropsychopharmacology & Biological Psychiatry
    Volume
    82
    DOI
    https://doi.org/10.1016/j.pnpbp.2017.11.028
    Copyright Statement
    © 2018 Progress in Neuropsychopharmacology & Biological Psychiatry, Published by Elsevier Ltd. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Subject
    Biomedical and clinical sciences
    Clinical sciences
    Clinical sciences not elsewhere classified
    Neurosciences
    Psychology
    Publication URI
    http://hdl.handle.net/10072/377091
    Collection
    • Journal articles

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