Regiospecific solid-phase synthesis of branched oligoribonucleotides that mimic intronic lariat RNA intermediates

Adam Katolik, Richard Johnsson, Eric Montemayor, Jeremy G. Lackey, P. John Hart, Masad J. Damha

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

We have developed new solid phase methods for the synthesis of branched RNAs that mimic intronic lariat RNA intermediates. These methods produce branched oligoribonucleotide sequences of arbitrary length, base composition, and regiochemistry at the branchpoint junction. The methods utilize branching monomers that allow for the growth of each branch regioselectively from any of the hydroxyl positions (5′, 3′, or 2′) at the branch-point junction. The integrity and branchpoint connectivity of the synthetic products have been confirmed by HPLC and MS analysis, and cleavage of the 2′,5′ linkage by recombinant debranching enzyme. Nonhydrolyzable branched RNA analogues containing arabinose instead of ribose at the branchpoint junction were shown to inhibit debranching activity and, hence, represent "decoys" for sequestering RNA binding proteins thought to drive amyotrophic lateral sclerosis (ALS).

Original languageEnglish (US)
Pages (from-to)963-975
Number of pages13
JournalJournal of Organic Chemistry
Volume79
Issue number3
DOIs
StatePublished - Feb 7 2014

ASJC Scopus subject areas

  • Organic Chemistry

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