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Harnessing the Activity of the Fungal Metalloprotease, Mpr1, To Promote Crossing of Nanocarriers through the Blood–Brain Barrier
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    Harnessing the Activity of the Fungal Metalloprotease, Mpr1, To Promote Crossing of Nanocarriers through the Blood–Brain Barrier
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    • Phylicia A. Aaron
      Phylicia A. Aaron
      Department of Pharmacology, School of Medicine, University of California, 3503 Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, California 95616, United States
    • Angie Gelli*
      Angie Gelli
      Department of Pharmacology, School of Medicine, University of California, 3503 Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, California 95616, United States
      *E-mail: [email protected]. Tel.: 530-754-6446.
      More by Angie Gelli
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    ACS Infectious Diseases

    Cite this: ACS Infect. Dis. 2020, 6, 1, 138–149
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    https://doi.org/10.1021/acsinfecdis.9b00348
    Published December 10, 2019
    Copyright © 2019 American Chemical Society

    Abstract

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    Cryptococcus neoformans (Cn) is the leading cause of fungal meningitis primarily in immunosuppressed patients. Cn invades the central nervous system by overcoming the highly restricted blood–brain barrier (BBB). We previously determined that a secreted fungal metalloprotease, Mpr1, that also confers crossing ability to yeast upon CnMPR1 expression in Saccharomyces cerevisiae is central to this process. This led us to question whether Mpr1 could be engineered to function as part of a nanocarrier delivery vehicle. Here, a eukaryotic expression system produced proteolytically active Mpr1 recombinant protein that was successfully conjugated to functionalized quantum dot (QD) nanoparticles and readily internalized by brain microvascular endothelial cells. An in vitro BBB model showed QD-Mpr1 crossed the BBB significantly better than mock QD, and QD-Mpr1 did not damage BBB integrity. Internalization of QD-Mpr1 occurred by membrane invaginations and endocytic pits typical of receptor-mediated endocytosis involving clathrin-coated entry points. This study substantiates the notion that fungal mechanisms of BBB entry may be harnessed for new drug delivery platform technologies.

    Copyright © 2019 American Chemical Society

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.9b00348.

    • Figure S1, quantitative PCR; Figure S2, MS/MS spectral analysis; Figure S3, amino acid sequence of Mpr1 protein from Cryptococcus neoformans var. grubii (strain H99) (PDF)

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    This article is cited by 10 publications.

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    10. Phylicia A. Aaron, Kiem Vu, Angie Gelli, . An Antivirulence Approach for Preventing Cryptococcus neoformans from Crossing the Blood-Brain Barrier via Novel Natural Product Inhibitors of a Fungal Metalloprotease. mBio 2020, 11 (4) https://doi.org/10.1128/mBio.01249-20

    ACS Infectious Diseases

    Cite this: ACS Infect. Dis. 2020, 6, 1, 138–149
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsinfecdis.9b00348
    Published December 10, 2019
    Copyright © 2019 American Chemical Society

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