• Open Access

Novel Cruzain Inhibitors for the Treatment of Chagas’ Disease

Authors

  • Kathleen E Rogers,

    Corresponding author
    1. Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093, USA
      Corresponding author: Kathleen Rogers,krogers@ucsd.edu
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  • Henrik Keränen,

    1. Department of Cell and Molecular Biology, Uppsala University, S-751 24 Uppsala, Sweden
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  • Jacob D. Durrant,

    1. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
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  • Joseline Ratnam,

    1. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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  • Allison Doak,

    1. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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  • Michelle R. Arkin,

    1. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA
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  • J. Andrew McCammon

    1. Department of Chemistry and Biochemistry, NSF Center for Theoretical Biological Physics, National Biomedical Computation Resource, University of California San Diego, La Jolla, CA 92093, USA
    2. Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA
    3. Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, USA
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Corresponding author: Kathleen Rogers,krogers@ucsd.edu

Abstract

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas’ disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas’ disease.

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