An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS-CoV Mpro) Inhibitors

Authors

  • Samer I. Al-Gharabli Dr.,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Department for Medicinal Chemistry, Robert-Rössle-Straße 10, 13125 Berlin, Germany, Fax: (+49) 30-94793-280
    2. Current address: Chemical and Pharmaceutical Engineering, German–Jordanian University, 35247 Amman 11180, Jordan
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  • Syed T. Ali Shah Dr.,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Department for Medicinal Chemistry, Robert-Rössle-Straße 10, 13125 Berlin, Germany, Fax: (+49) 30-94793-280
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  • Steffen Weik Dr.,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Department for Medicinal Chemistry, Robert-Rössle-Straße 10, 13125 Berlin, Germany, Fax: (+49) 30-94793-280
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  • Marco F. Schmidt Dipl.-Biochem.,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Department for Medicinal Chemistry, Robert-Rössle-Straße 10, 13125 Berlin, Germany, Fax: (+49) 30-94793-280
    2. Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany
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  • Jeroen R. Mesters Dr.,

    1. Institut für Biochemie, Center for Structural and Cell Biology in Medicine, Universität Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
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  • Daniel Kuhn Dr.,

    1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany
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  • Gerhard Klebe Prof. Dr.,

    1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany
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  • Rolf Hilgenfeld Prof. Dr.,

    1. Institut für Biochemie, Center for Structural and Cell Biology in Medicine, Universität Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
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  • Jörg Rademann Prof. Dr.

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Department for Medicinal Chemistry, Robert-Rössle-Straße 10, 13125 Berlin, Germany, Fax: (+49) 30-94793-280
    2. Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany
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Abstract

A method for the parallel solid-phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization-free oxidation of amino alcohols with Dess–Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N-protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS-CoV Mpro(also known as 3CLpro), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS-CoV Mpro. Several potent inhibitors were found with IC50 values in the low micromolar range. An IC50 of 7.5 μM was found for AcNSTSQ-H and AcESTLQ-H. Interestingly, the most potent inhibitors seem to bind to SARS-CoV Mpro in a noncanonical binding mode.

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