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J Org Chem. 2015 Oct 16;80(20):10108-18. doi: 10.1021/acs.joc.5b01719. Epub 2015 Sep 30.

Design, Synthesis, and Properties of Phosphoramidate 2',5'-Linked Branched RNA: Toward the Rational Design of Inhibitors of the RNA Lariat Debranching Enzyme.

Author information

1
Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
2
Department of Life Science, Tokyo Institute of Technology , 4259 Nagatsuta, Midoriku, Yokohama, Kanagawa 226-8501, Japan.
3
Department of Veterans Affairs, South Texas Veterans Health Care System , San Antonio, Texas 78229, United States.
4
Departments of Biochemistry and Biomolecular Chemistry, University of Wisconsin-Madison , 433 Babcock Dr., Madison, Wisconsin 53706, United States.
5
Department of Biochemistry, University of Texas Health Science Center , 7703 Floyd Curl Drive, San Antonio, Texas 78229, United States.

Abstract

Two RNA fragments linked by means of a 2',5' phosphodiester bridge (2' hydroxyl of one fragment connected to the 5' hydroxyl of the other) constitute a class of nucleic acids known as 2'-5' branched RNAs (bRNAs). In this report we show that bRNA analogues containing 2'-5' phosphoramidate linkages (bN-RNAs) inhibit the lariat debranching enzyme, a 2',5'-phosphodiesterase that has recently been implicated in neurodegenerative diseases associated with aging. bN-RNAs were efficiently generated using automated solid-phase synthesis and suitably protected branchpoint building blocks. Two orthogonally removable groups, namely the 4-monomethoxytrityl (MMTr) group and the fluorenylmethyl-oxycarbonyl (Fmoc) groups, were evaluated as protecting groups of the 2' amino functionality. The 2'-N-Fmoc methodology was found to successfully produce bN-RNAs on solid-phase oligonucleotide synthesis. The synthesized bN-RNAs resisted hydrolysis by the lariat debranching enzyme (Dbr1) and, in addition, were shown to attenuate the Dbr1-mediated hydrolysis of native bRNA.

PMID:
26378468
PMCID:
PMC4749351
DOI:
10.1021/acs.joc.5b01719
[Indexed for MEDLINE]
Free PMC Article

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