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

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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
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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 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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Progress in Neuropsychopharmacology & Biological Psychiatry

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82

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© 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.

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Biomedical and clinical sciences

Clinical sciences

Clinical sciences not elsewhere classified

Neurosciences

Psychology

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