Immunosuppressive Small Molecule Discovered by Structure-Based Virtual Screening for Inhibitors of Protein–Protein Interactions

Authors

  • Tim Geppert,

    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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  • Stefanie Bauer,

    1. Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, 63225 Langen (Germany)
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  • Dr. Jan A. Hiss,

    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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  • Elea Conrad,

    1. Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, 63225 Langen (Germany)
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  • Michael Reutlinger,

    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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  • Dr. Petra Schneider,

    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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  • Dr. Martin Weisel,

    1. Goethe-Universität Frankfurt, Institut für Organische Chemie und Chemische Biologie, Beilstein-Stiftungsprofessur, Frankfurt (Germany)
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  • Bernhard Pfeiffer,

    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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  • Prof. Dr. Karl-Heinz Altmann,

    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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  • Priv.-Doz. Dr. Zoe Waibler,

    1. Junior Research Group “Novel Vaccination Strategies and Early Immune Responses”, Paul-Ehrlich-Institut, 63225 Langen (Germany)
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    • These authors contributed equally to this work.

  • Prof. Dr. Gisbert Schneider

    Corresponding author
    1. Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
    • Eidgenössische Technische Hochschule (ETH) Zürich, Department of Chemistry and Applied Biosciences, Wolfgang-Pauli-Strasse 10, 8093 Zürich (Switzerland)
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    • These authors contributed equally to this work.


  • We thank Kay-Martin Hanschmann and Peter Volkers for statistical analyses, and Gerd Sutter for providing MVA. Martin Löwer implemented the VirtualLigand software. The Chemical Computing Group Inc. kindly provided a research license for MOE. This research was supported by the Swiss National Science Foundation (grant 205321-134783), the OPO-Foundation Zurich (G.S.), and the Deutsche Forschungsgemeinschaft (grant WA 2873/1-1 to Z.W.).

Abstract

original image

Interfering with interferon: A low-molecular-weight inhibitor has been discovered that blocks the interaction between interferon-α (IFN-α) and its receptor (see picture for a model of the interfaces). The resulting lead compound significantly reduces IFN-α production in vitro. NMR and SPR experiments confirm the direct interaction of the inhibitor with IFN-α.

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