Affinity-based purification of oligonucleotides using soluble multimeric oligonucleotides

DETAILED DESCRIPTION The present invention provides novel multimeric oligonucleotides and their use for the purification of antisense oligonucleotides through complementary base recognition and size exclusion principles.
In a particular embodiment, the invention provides compounds and methods for the purification of full length synthetic oligonucleotides from a solution also containing N-1 and other failure sequences generated during synthesis.
The oligonucleotides of the invention are of a unique structure that allows them to hybridize specifically with a desired, full-length oligonucleotide and concomitantly form multimer aggregates.
The desired oligonucleotide is thereby bound in a multimer aggregate while other undesired oligonucleotides remain in solution.
The desired oligonucleotide is then separated and isolated using size-exclusion techniques.
In one aspect of the invention, the oligonucleotides according to the invention have at least three structural features: (1) a multimerization domain, (2) a hybridization domain, and (3) a linker domain.
The multimerization domain comprises a sequence of nucleotides that induces interoligonucleotide aggregate formation.
The hybridization domain comprises a sequence of nucleotides that is complementary to the 5' end of a synthetic oligonucleotide whose purification is desired.
The linker domain comprises a sequence of nucleotides or non-nucleotide chemical moieties and serves both to link the hybridization domain to the multimerization domain as well as space the hybridization domain away from the multimerization domain to allow for simultaneous aggregate formation and hybridization to the target oligonucleotide.
When contacted with a crude solution containing the desired oligonucleotide and other failure sequences generated during synthesis, the hybridization domain hybridizes to the desired ("target") oligonucleotide but not to the failure sequences, which are insufficiently complementary to hybridize to the hybridization domain under the conditions chosen