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Novel Methods for the Reversible Incorporation of Functional Groups into RNA and DNA: Synthesis and Uses for 2'-O-aminooxymethyl Nucleoside Derivatives

Novel Methods for the Reversible Incorporation of Functional Groups into RNA and DNA: Synthesis and Uses for 2'-O-aminooxymethyl Nucleoside Derivatives

The delivery of DNA/RNA therapeutic drugs is still a major hurdle for the clinical application of DNA/RNA-based drugs. Also, developments in silencing the expression of specific genes, through RNA interference pathways, have led to an increased demand for synthetic RNA sequences and have created a pressing need for rapid and efficient methods for RNA synthesis. Recently, FDA scientists have developed a novel phosphoramidite, 2’-O-aminooxymethyl ribonucleoside (2’-O-protected compounds). The 2’-O-aminooxymethyl ribonucleoside can be modified with any type of functional group using an oximation reaction as long as the functional group contains an aldehyde, ketone, or acetal group. Modification of the 2’-O-aminooxymethyl with an aldehyde results in a conjugated 2’-phosphoramidite that could be readily converted back to the native ribonucleoside and its corresponding by-product. On the other hand, the oximation of 2’-O-aminooxymethy with a ketone results in an irreversible conjugated form of the phosphoramidite.

The 2’-O-protected compounds of the present technology have several advantages, for example, the 2’-O-protected compound is stable during the various reaction steps involved in oligonucleotide synthesis; and the protecting group can be easily removed after the synthesis of the oligonucleotide, for example, by reaction with tetrabutylammonium fluoride; and the O-protected groups do not generate DNA/RNA alkylating side products, which have been reported during removal of 2’-O-(2-cyanoethyl)oxymethyl or 2’-O-[2-(4-tolylsulfonyl)ethoxymethyl groups under similar conditions.

Potential Commercial Applications:

  • Incorporation of a potentially large array of functional groups into RNA and DNA oligonucleotides for diagnostic and/or therapeutic applications.
  • Conjugation of a variety of sugars or complex carbohydrates to DNA/RNA therapeutic oligonucleotides.
  • Attachment of cell membrane-penetrating peptides to therapeutic DNA/RNA oligonucleotides.

Competitive Advantages:

 


Inventors:
Serge Beaucage
Jacek Cieslak

Intellectual Property:
US Application No. 14/008,805
PCT Application No. PCT/US2012/031107

Licensing Contact:
Bill Ronnenberg, JD-MIP, MS
FDA Technology Transfer Program
10903 New Hampshire Ave.
Building WO1, Rm 4214
Silver Spring, MD 20993
Email: FDAInventionlicensing@fda.hhs.gov
Phone: 240-402-4561

OTT Reference No: E-262-2010/0
Updated: August 6, 2015