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    1H-imidazole-2,5-dicarboxamides as ns4a peptidomimetics: Identification of a new approach to inhibit hcv-ns3 protease

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    biomolecules-10-00479.pdf
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    Description:
    Accepted manuscript
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    Type
    Article
    Authors
    Omar, Abdelsattar M. cc
    Elfaky, Mahmoud A. cc
    Arold, Stefan T. cc
    Soror, Sameh H. cc
    Khayat, Maan T.
    Asfour, Hani Z.
    Bamane, Faida H.
    El-Araby, Moustafa E. cc
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    Computational Bioscience Research Center (CBRC)
    Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
    Structural Biology and Engineering
    Date
    2020-03-21
    Submitted Date
    2020-02-06
    Permanent link to this record
    http://hdl.handle.net/10754/662444
    
    Metadata
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    Abstract
    The nonstructural (NS) protein NS3/4A protease is a critical factor for hepatitis C virus (HCV) maturation that requires activation by NS4A. Synthetic peptide mutants of NS4A were found to inhibit NS3 function. The bridging from peptide inhibitors to heterocyclic peptidomimetics of NS4A has not been considered in the literature and, therefore, we decided to explore this strategy for developing a new class of NS3 inhibitors. In this report, a structure-based design approach was used to convert the bound form of NS4A into 1H-imidazole-2,5-dicarboxamide derivatives as first generation peptidomimetics. This scaffold mimics the buried amino acid sequence Ile-25‘ to Arg-28‘ at the core of NS4A21‘–33‘ needed to activate the NS3 protease. Some of the synthesized compounds (Coded MOC) were able to compete with and displace NS4A21‘–33‘ for binding to NS3. For instance, N5-(4-guanidinobutyl)-N2-(n-hexyl)-1H-imidazole-2,5-dicarboxamide (MOC-24) inhibited the binding of NS4A21‘–33‘ with a competition half maximal inhibitory concentration (IC50) of 1.9 ± 0.12 µM in a fluorescence anisotropy assay and stabilized the denaturation of NS3 by increasing the aggregation temperature (40% compared to NS4A21‘–33‘). MOC-24 also inhibited NS3 protease activity in a fluorometric assay. Molecular dynamics simulations were conducted to rationalize the differences in structure–activity relationship (SAR) between the active MOC-24 and the inactive MOC-26. Our data show that MOC compounds are possibly the first examples of NS4A peptidomimetics that have demonstrated promising activities against NS3 proteins.
    Citation
    Omar, A. M., Elfaky, M. A., Arold, S. T., Soror, S. H., Khayat, M. T., Asfour, H. Z., … El-Araby, M. E. (2020). 1H-Imidazole-2,5-Dicarboxamides as NS4A Peptidomimetics: Identification of a New Approach to Inhibit HCV-NS3 Protease. Biomolecules, 10(3), 479. doi:10.3390/biom10030479
    Sponsors
    This project was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, the Kingdom of Saudi Arabia; Award number 12-BIO3193-03. The research reported in this publication was also supported by funding from King Abdullah University of Science and Technology (KAUST). The authors acknowledge, with thanks, the Science and Technology Unit, King Abdulaziz University for technical support. Authors are exceptionally grateful to MDPI, the Editor Ms. Sophia Lin, and the respected reviewers for being very cooperative to publish this manuscript, considering the current circumstances of the COVID-19 pandemic that hindered us from covering some reviewers’ comments.
    Publisher
    MDPI AG
    Journal
    Biomolecules
    DOI
    10.3390/biom10030479
    PubMed ID
    32245218
    Additional Links
    https://www.mdpi.com/2218-273X/10/3/479
    ae974a485f413a2113503eed53cd6c53
    10.3390/biom10030479
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program; Computational Bioscience Research Center (CBRC); Computer, Electrical and Mathematical Science and Engineering (CEMSE) Division

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