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    Solid-Phase Synthesis of Difficult Purine-Rich PNAs through Selective Hmb Incorporation: Application to the Total Synthesis of Cell Penetrating Peptide-PNAs

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    Author
    Tailhades, J; Takizawa, H; Gait, MJ; Wellings, DA; Wade, JD; Aoki, Y; Shabanpoor, F
    Date
    2017-10-17
    Source Title
    Frontiers in Chemistry
    Publisher
    FRONTIERS MEDIA SA
    University of Melbourne Author/s
    Wade, John; Shabanpoor, Fazel; TAILHADES, JULIEN
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Metadata
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    Document Type
    Journal Article
    Citations
    Tailhades, J., Takizawa, H., Gait, M. J., Wellings, D. A., Wade, J. D., Aoki, Y. & Shabanpoor, F. (2017). Solid-Phase Synthesis of Difficult Purine-Rich PNAs through Selective Hmb Incorporation: Application to the Total Synthesis of Cell Penetrating Peptide-PNAs. FRONTIERS IN CHEMISTRY, 5 (Oct), https://doi.org/10.3389/fchem.2017.00081.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257502
    DOI
    10.3389/fchem.2017.00081
    Abstract
    Antisense oligonucleotide (ASO)-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino) and Spinraza (2'-O-methoxyethyl-phosphorothioate) in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA) chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here, we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl) and Dmb (2,4-dimethoxybenzyl) to ameliorate difficult couplings and reduce "on-resin" aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences.

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