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Synthesis and Evaluation of Peptidyl Michael Acceptors That Inactivate Human Rhinovirus 3C Protease and Inhibit Virus Replication

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    Synthesis and Evaluation of Peptidyl Michael Acceptors That Inactivate Human Rhinovirus 3C Protease and Inhibit Virus Replication
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    Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506, and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1998, 41, 14, 2579–2587
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    https://doi.org/10.1021/jm980114+
    Published June 16, 1998
    Copyright © 1998 American Chemical Society
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    Abstract

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    Human rhinovirus, the chief cause of the common cold, contains a positive-sense strand of RNA which is translated into a large polyprotein in infected cells. Cleavage of the latter to produce the mature viral proteins required for replication is catalyzed in large part by a virally encoded cysteine proteinase (3Cpro) which is highly selective for −Q∼GP− cleavage sites. We synthesized peptidyl derivatives of vinylogous glutamine or methionine sulfone esters (e.g., Boc-Val-Leu-Phe-vGln-OR:  R = Me, 1; R = Et, 2) and evaluated them as inhibitors of HRV-14 3C protease (3Cpro). Compounds 1 and 2 and several related tetra- and pentapeptide analogues rapidly inactivated 3Cpro with submicromolar IC50 values. Electrospray mass spectrometry confirmed the expected 1:1 stoichiometry of 3Cpro inactivation by 1, 2, and several other analogues. Compound 2 also proved to be useful for active site titration of 3Cpro, which has not been possible heretofore because of the lack of a suitable reagent. In contrast to 1, 2, and congeners, peptidyl Michael acceptors lacking a P4 residue have greatly reduced or negligible activity against 3Cpro, consistent with previously established structure−activity relationships for 3Cpro substrates. Hydrolysis of the P1 vinylogous glutamine ester to a carboxylic acid also decreased inhibitory activity considerably, consistent with the decreased reactivity of acrylic acids vs acrylic esters as Michael acceptors. Incorporating a vinylogous methionine sulfone ester in place of the corresponding glutamine derivative in 1 also reduced activity substantially. Compounds 1 and 2 and several of their analogues inhibited HRV replication in cell culture by 50% at low micromolar concentrations while showing little or no evidence of cytotoxicity at 10-fold higher concentrations. Peptidyl Michael acceptors and their analogues may prove useful as therapeutic agents for pathologies involving cysteine proteinase enzymes.

    Copyright © 1998 American Chemical Society

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    †

     University of Kansas.

    ‡

     Eli Lilly and Co.

    *

     Address correspondence to:  Dr. Robert P. Hanzlik at University of Kansas. Tel:  785-864-3750. Fax:  785-864-5326. E-mail:  rhanzlik@ rx.pharm.ukans.edu.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 1998, 41, 14, 2579–2587
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm980114+
    Published June 16, 1998
    Copyright © 1998 American Chemical Society
    Request reuse permissions

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