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    Small-molecule inhibitors for the Prp8 intein as antifungal agents

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    Author
    Li, Zhong
    Tharappel, Anil Mathew
    Xu, Jimin
    Lang, Yuekun
    Green, Cathleen M.
    Zhang, Jing
    Lin, Qishan
    Chaturvedi, Sudha
    Zhou, Jia
    Belfort, Marlene
    Li, Hongmin
    Show allShow less
    Affiliation
    Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona
    Issue Date
    2021-01-04
    Keywords
    Small-molecule inhibitor
    Antifungal
    Cryptococcus
    PRP8 intein
    Protein splicing
    
    Metadata
    Show full item record
    Publisher
    Proceedings of the National Academy of Sciences
    Citation
    Li, Z., Tharappel, A. M., Xu, J., Lang, Y., Green, C. M., Zhang, J., ... & Li, H. (2021). Small-molecule inhibitors for the Prp8 intein as antifungal agents. Proceedings of the National Academy of Sciences, 118(2), e2008815118.
    Journal
    Proceedings of the National Academy of Sciences of the United States of America
    Rights
    © 2021 The Author(s). Published under the PNAS license.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Self-splicing proteins, called inteins, are present in many human pathogens, including the emerging fungal threats Cryptococcus neoformans (Cne) and Cryptococcus gattii (Cga), the causative agents of cryptococcosis. Inhibition of protein splicing in Cryptococcus sp. interferes with activity of the only intein-containing protein, Prp8, an essential intron splicing factor. Here, we screened a small-molecule library to find addititonal, potent inhibitors of the Cne Prp8 intein using a split-GFP splicing assay. This revealed the compound 6G-318S, with IC50 values in the low micromolar range in the split-GFP assay and in a complementary split-luciferase system. A fluoride derivative of the compound 6G-318S displayed improved cytotoxicity in human lung carcinoma cells, although there was a slight reduction in the inhibition of splicing. 6G-318S and its derivative inhibited splicing of the Cne Prp8 intein in vivo in Escherichia coli and in C. neoformans. Moreover, the compounds repressed growth of WT C. neoformans and C. gattii. In contrast, the inhibitors were less potent at inhibiting growth of the inteinless Candida albicans. Drug resistance was observed when the Prp8 intein was overexpressed in C. neoformans, indicating specificity of this molecule toward the target. No off-target activity was observed, such as inhibition of serine/cysteine proteases. The inhibitors bound covalently to the Prp8 intein and binding was reduced when the active-site residue Cys1 was mutated. 6G-318S showed a synergistic effect with amphotericin B and additive to indifferent effects with a few other clinically used antimycotics. Overall, the identification of these small-molecule intein-splicing inhibitors opens up prospects for a new class of antifungals.
    Note
    6 month embargo; published online: 4 January 2021
    ISSN
    0027-8424
    EISSN
    1091-6490
    DOI
    10.1073/pnas.2008815118
    Version
    Final accepted manuscript
    Sponsors
    HHS | NIH | National Institute of Allergy and Infectious Diseases
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.2008815118
    Scopus Count
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    UA Faculty Publications

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