Modified internucleoside linkages (ii)
AssigneeIsis Pharmaceuticals, Inc.
InventorsSundaramoorthi Swaminathan, Mark Matteucci, Jeff Pudlo, Robert J. Jones
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Abstract
The invention relates to novel modified oligonucleotides, the construction thereof, and their use in oligonucleotide-based therapies. More specifically, the invention is to novel oligonucleotides having modified internucleoside linkages which are resistant to nucleases, having enhanced ability to penetrate cells, and which are capable of binding target oligonucleotide sequences in vitro and in vivo. The modified oligonucleotides of the invention are particularly useful in oligonucleotide-based therapies utilizing the modified oligonucleotides to interrupt protein synthesis or transcription or to otherwise inactivate messenger RNA or double stranded DNA.
Claims16
A modified oligonucleotide or derivative thereof, wherein the modification comprises substitution, for one or more phosphodiester linkages between 2′ and 5′ position of adjacent nucleosides, with a two to three atom long internucleoside linkage wherein at least one of the atoms making up the internucleoside linkage is selected from nitrogen, oxygen, or sulfur, with the remainder being carbon provided that no adjacent two or three atoms are oxygen nor adjacent three atoms are all oxygen, nitrogen, or sulfur.
A modified oligonucleotide or derivative thereof, wherein the modification comprises substitution, for one or more phosphodiester linkages between 2′ and 5′ position of adjacent nucleosides, with a two to three atom long internucleoside linkage wherein at least one of the atoms making up the internucleoside linkage is nitrogen, oxygen, and sulfur, with the remainder being carbon wherein the internucleoside linkages are independently selected from the group of:
- 77
- wherein R6 is H, lower alkyl, OMe, OH, heteroalkyl, or aryl;
- and
- wherein R8 is CH2F, or when both R8 are taken together witn the atom to which they are attached, form a 4-membered or 6-membered ring where (R8)2 is
- —CH2—X1—CH2—, or
- —(CH2)2—X1—(CH2)2—;
- wherein X1 is selected from the group consisting of NH, NMe, NEt, NPr, S, SO, SO2, O, CF2 and CHF.
An oligomer of the formula (W,Y)—Q—(Z-Q)n,—(W,Y) or a derivative thereof, where each
- 80
- where X is S, O, CH2, CHF or CF2,
- R1 independently is —O-alkyl (C1-C12), —S-alkyl (C1-C12), H, OH, OCH3, SCH3, OC3H5 (O-allyl), OC3C7 (O-propyl), SC3H5, or F and
- where R1 is on a terminal group of the oligomer, R1 may additionally be PO3−2 or a blocking group selected from a dimethoxytrityl (DMT) moiety, a monomethoxytrityl (MMT) moiety, H-phosphonate (OPO2H), methylphosphonate (OPO2CH3) or phosphoramidite;
- and
- B is independently a purine or pyrimidine residue or an analogous residue, and
- Q is independently
- a phosphodiester analog or
- a two to four atom long internucleoside linkage
- wherein at least one of the atoms making up the internucleoside linkage is selected from nitrogen, oxygen or sulfur, with the remainder being carbon but no two adjacent atoms are oxygen nor any adjacent three atoms are all oxygen, nitrogen or sulfur;
- and
- n is 1-100, and
- subject to the proviso that at least one Q is not a phosphodiester analog.
An oligomer of the formula
- (W,Y)—Q—(Z-Q)n—(W,Y)
- or a derivative thereof, where each
- 81
- where X is S, O, CH2, CHF or CF2,
- R1 independently is —O-alkyl (C1-C12), —S-alkyl (C1-C12), H, OH, OCH3, SCH3, OC3H5 (O-allyl), OC3C7(O-propyl), SC3H5, or F and
- where R1 is on a terminal group of the oligomer, R1 may additionally be PO3−2 or a blocking group selected from a dimethoxytrityl (DMT) moiety, a monomethoxytrityl (MMT) moiety, H-phosphonate (OPO2H), methylphosphonate (OPO2CH3) or phosphoramidite;
- and
- B is independently a purine or pyrimidine residue or an analogous residue, and
- Q is independently
- a phosphodiester analog or
- a two to three atom long internucleoside linkage
- wherein at least one of the atoms making up the internucleoside linkage is selected from nitrogen, oxygen or sulfur, but no two adjacent atoms are oxygen, with the remainder being carbon wherein the internucleoside linkages are independently selected from the group of:
- 82
- wherein R6 is H, lower alkyl, OMe, OH, heteroalkyl, or aryl;
- and
- wherein R8 is CH2F, or when both R8 are taken together with the atom to which they are attached, form a 4-membered or 6-membered ring where (R6)2 is
- —CH2—X1—CH2—,
- —(CH2)2—X1—(CH2)2—;
- wherein X1 is selected from the group consisting of NH, NMe, NEt, NPr, S, SO, SO2, O, CF2 and CHF;
- n is 1-100, and
- subject to the proviso that at least one Q is not a phosphodiester analog.
Dependencies are inferred from the claim text.