Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-05-13
2001-12-18
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S004100, C536S022100, C536S023100, C536S025410, C530S300000, C530S333000, C530S350000, C544S116000, C544S218000
Reexamination Certificate
active
06331618
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to the field of nucleic acid analogs with uncharged, neutral backbones. Specifically, this invention is directed to aqueous mixtures of polar aprotic solvents that enable high-concentration dissolution of peptide nucleic acids (PNA).
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BACKGROUND
Nucleic acid analogs, including peptide nucleic acids (PNA), internucleotide analogs, and nucleobase analogs, are often studied and characterized by analytical tests and methods at substantially higher concentrations than physiological concentrations under metabolic conditions (Alberts, 1989). Some tests, methods and experiments that may require high concentrations of nucleic acid analogs are intracellular antisense inhibition of transcription and translation of sense DNA and mRNA, labelling of nucleic acid analog reactions, and attaching nucleic acid analogs to surfaces of other heterogeneous media. Analytical methods that may require high concentrations of nucleic acid analogs are gel electrophoresis (Rickwood, 1990), high-performance liquid chromatography (HPLC) (Oliver, 1998), primer extension reactions, polymerase chain reaction (PCR), mass spectroscopy, nuclear magnetic resonance (NMR) and X-ray crystallization.
Nucleic acid analogs with uncharged, neutral backbones, such as peptide-nucleic acids (PNA) (Buchardt, 1992), morpholino-carbamate (Summerton, 1991), methyl phosphonate oligonucleotides (Miller, 1991), and others (Goodnow, 1998) have the advantage of nuclease-resistance for prolonged in vivo stability but are notoriously difficult to solubilize and maintain in aqueous solution, particularly at neutral pH. Such uncharged analogs lack the solubility-facilitating phosphate anions of DNA and RNA. PNA sequences with a N-(2-aminoethyl)-glycine polymer backbone and high purine nucleobase content can be especially difficult to solubilize (Nielsen, 1991). Useful concentrations of PNA sequences with contiguous thymidine nucleobases are also sometimes difficult to achieve. Typically, PNA are dissolved in low pH, primarily aqueous solutions. PNA nucleobases are basic and become protonated and charged at low pH, increasing their solubility under acidic conditions. For the most part, nucleic acid analogs such as PNA are not appreciably soluble in neutral, aqueous conditions. If solution is achieved at neutral pH by elevated temperature, agitation, or other techniques, nucleic acid analogs are prone to precipitation when allowed to stand at or below room temperature. F
Bloch William
Egholm Michael
Myers Rene L.
Werner William E.
Andrus Alex
PE Corporation (NY)
Wilson James O.
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