Single-stranded oligonucleotide

Abstract

A single-stranded oligonucleotide that can be easily produced and that regulates target genes with high efficiency is provided. [Solution] A single-stranded oligonucleotide represented by formula (I) in which X and Y hybridize at a first nucleotide sequence portion and a second nucleotide sequence portion, respectively. X has a first nucleotide sequence consisting of 7 to 100 nucleotides, containing at least one modified nucleotide, and capable of hybridizing with a second oligonucleotide. Y has a second nucleotide sequence consisting of 4 to 100 nucleotides, containing at least one ribonucleotide, capable of hybridizing with the first oligonucleotide. At least one of the nucleotide sequences X, Xz, and Y has an antisense sequence capable of hybridizing with a target RNA. At least one of L, Lx, and Ly is a linking group containing a non-nucleotide structure. TIFF2023025156000262.tif14161

Description

[Technical Field]

[0001] The present invention relates to single-stranded oligonucleotides. [Background technology]

[0002] Antisense oligonucleotides (ASOs) are oligonucleotides complementary to the mRNA, pre-mRNA, or non-coding RNA (ncRNA) of a target gene, such as ribosomal RNA, transfer RNA, or miRNA. They are single-stranded DNA, RNA, and / or structural analogs thereof, consisting of approximately 8 to 30 bases. ASOs inhibit the activity of the target mRNA, pre-mRNA, or ncRNA by forming a duplex with the antisense oligonucleotide.

[0003] However, ASOs are difficult to put into practical use because they are easily degraded by nucleases in the body and have low uptake efficiency into target cells. To overcome these two major problems, research has been conducted for many years on chemical modification of the active ingredient, oligonucleotides themselves, and drug delivery systems (DDS) that deliver oligonucleotides into target cells.

[0004] Known examples of chemical modifications of ASOs themselves include S-oligos (phosphorothioates) in which the phosphate moiety is modified, and 2',4'-BNA (bridged nucleic acid) / LNA (locked nucleic acid) in which the sugar moiety is modified (see Patent Documents 1 to 5).

[0005] Known examples of DDS include methods that utilize carriers such as cationic liposomes and polymeric micelles. Patent Document 6 describes an ASO in which a GalNAc (N-acetylgalactosamine) derivative, a sugar derivative that interacts with the asialoglycoprotein receptor, is linked via a linker, and describes that administration of this ASO suppressed the expression of a target gene in the liver.

[0006] Patent Document 7 and Non-Patent Document 1 describe that by binding tocopherol (Toc) to a double-stranded oligonucleotide (HDO) containing an RNA oligonucleotide complementary to an ASO, it was delivered to and accumulated in the liver more efficiently than ASO, and target gene expression in the liver was suppressed in mice. Patent Document 8 describes an ASO in which a GalNAc derivative is bound to HDO via a linker, and describes that when this antisense oligonucleotide was administered subcutaneously, expression was suppressed more efficiently than in a tocopherol (Toc)-modified form.

[0007] Patent document 9 describes that an oligonucleotide (HCDO) in which an ASO is bound to the RNA strand end of a double-stranded oligonucleotide unit of DNA and RNA suppresses target RNA more efficiently than an ASO. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 98 / 39352 [Patent Document 2] International Publication No. 2005 / 021570 [Patent Document 3] International Publication No. 2003 / 068795 [Patent Document 4] International Publication No. 2011 / 052436 [Patent Document 5] International Publication No. 2011 / 156202 [Patent Document 6] International Publication No. 2014 / 179620 [Patent Document 7] International Publication No. 2013 / 089283 [Patent Document 8] International Publication No. 2015 / 105083 [Patent Document 9] International Publication No. 2014 / 192310 [Non-patent literature]

[0009] [Non-Patent Document 1] Nature Communications, Vol. 6, Article Number: 7969 (2015) Summary of the Invention [Problem to be solved by the invention]

[0010] For clinical application as pharmaceuticals in mammals, including humans, new nucleic acid drugs that can efficiently control target gene expression are desired. Furthermore, the production of double-stranded oligonucleotides (e.g., the aforementioned HDO and HCDO) requires the separate synthesis of an antisense strand and a complementary RNA strand, followed by a final hybridization step. Furthermore, when administered to animals or cells, dissociation into single strands must be suppressed, and the establishment of handling conditions is expected to be laborious.

[0011] An object of the present invention is to provide a novel oligonucleotide that can highly efficiently control the expression of a target gene, and also to provide an oligonucleotide that can be produced more easily than a double-stranded oligonucleotide. [Means for solving the problem]

[0012] The present inventors have discovered that linking an antisense oligonucleotide and its complementary strand containing RNA via a linker containing a non-nucleotide structure to form a single-stranded oligonucleotide with a structure that partially hybridizes within the molecule, or linking an oligodeoxyribonucleotide or the like with its complementary strand containing RNA via a linker containing a non-nucleotide structure to form a single-stranded oligonucleotide with a structure that partially hybridizes within the molecule, and that the single-stranded oligonucleotide has an antisense sequence that can control the expression of a target gene, thereby exhibiting antisense effects equivalent to or greater than those of double-stranded oligonucleotides. Furthermore, the inventors have discovered that linking the oligodeoxyribonucleotide and its complementary strand containing RNA via an oligonucleotide and using the linker containing a non-nucleotide structure to bind one of the oligonucleotide strands of the double-stranded oligonucleotide (e.g., binding the RNA strand of the HCDO to the ASO) also exhibits antisense effects equivalent to or greater than those of double-stranded oligonucleotides. Furthermore, because the single-stranded oligonucleotide is single-stranded, it can be efficiently produced without the need for the complicated hybridization step required to form a double strand. The present invention includes the following aspects.

[0013] 1. The following formula (I): [ka] wherein X is consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, a group derived from a first oligonucleotide comprising at least one nucleotide modified in at least one of the sugar moiety, the base moiety, and the phosphate moiety; Y is a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one ribonucleotide; Xz is a group derived from a third oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, Yz is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, L is Linking groups containing non-nucleotide structures, or of the formula: [ka] (In the formula, P 5 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 5 is a group derived from an oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), Lx is -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the formula: [ka] (In the formula, P 6 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 6 is a group derived from an oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), Ly is, -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the formula: [ka] (In the formula, P 7 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W7 is a group derived from an oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), at least one of L, Lx, and Ly is a linking group containing the non-nucleotide structure; L is covalently bonded at both ends to the first oligonucleotide and the second oligonucleotide, respectively; Lx is covalently bound to the first oligonucleotide and the third oligonucleotide at both ends thereof, Ly is covalently bound at both ends to the second oligonucleotide and the fourth oligonucleotide, respectively; m and n each independently represent 0 or 1; the first oligonucleotide has a nucleotide sequence X, the second oligonucleotide has a nucleotide sequence Y, the third oligonucleotide has a nucleotide sequence Xz, and the fourth oligonucleotide has a nucleotide sequence Yz; the nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing to at least a portion of a second oligonucleotide; the nucleotide sequence Y comprises a second nucleotide sequence capable of hybridizing to at least a portion of the first oligonucleotide and comprising at least one ribonucleotide; At least one of the nucleotide sequence X, the nucleotide sequence Xz, and the nucleotide sequence Yz comprises an antisense sequence capable of hybridizing with a target RNA; When there are two or more antisense sequences, the target RNAs to which the respective antisense sequence portions hybridize may be the same or different. wherein X and Y hybridize at the first nucleotide sequence portion and the second nucleotide sequence portion.

[0014] 2. Formula (I): [ka] wherein X is consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, a group derived from a first oligonucleotide comprising at least one nucleotide modified in at least one of the sugar moiety, the base moiety, and the phosphate moiety; Y is a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one ribonucleotide; Xz is a group derived from a third oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, Yz is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, L is Linking groups containing non-nucleotide structures, or of the formula: [ka] (In the formula, W 5 is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), Lx is -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the formula: [ka] (In the formula, W 6is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), Ly is, -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the formula: [ka] (In the formula, W 7 is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), at least one of L, Lx, and Ly is a linking group containing the non-nucleotide structure; L is covalently bonded at both ends to the first oligonucleotide and the second oligonucleotide, respectively; Lx is covalently bound to the first oligonucleotide and the third oligonucleotide at both ends thereof, Ly is covalently bound at both ends to the second oligonucleotide and the fourth oligonucleotide, respectively; m and n each independently represent 0 or 1; the first oligonucleotide has a nucleotide sequence X, the second oligonucleotide has a nucleotide sequence Y, the third oligonucleotide has a nucleotide sequence Xz, and the fourth oligonucleotide has a nucleotide sequence Yz; the nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing to at least a portion of a second oligonucleotide; the nucleotide sequence Y comprises a second nucleotide sequence capable of hybridizing to at least a portion of the first oligonucleotide and comprising at least one ribonucleotide; At least one of the nucleotide sequence X, the nucleotide sequence Xz, and the nucleotide sequence Yz comprises an antisense sequence capable of hybridizing with a target RNA; When there are two or more antisense sequences, the target RNAs to which the respective antisense sequence portions hybridize may be the same or different. wherein X and Y hybridize at the first nucleotide sequence portion and the second nucleotide sequence portion.

[0015] 3. The single-stranded oligonucleotide according to 1. or 2., wherein X is bound to L on the 3' side and Y is bound to L on the 5' side.

[0016] 4. The single-stranded oligonucleotide according to 1. or 2., wherein X is bound to L on the 5' side and Y is bound to L on the 3' side.

[0017] 5. The linking groups containing a non-nucleotide structure each independently represent the following formula: [ka] {where, V 11 teeth, C 2-50 Alkylene group (C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more independently selected substituents from The following formulas (XIII-1) to (XIII-11): [ka] (In the formula, о 1 is an integer between 0 and 30, and p 1 is an integer between 0 and 30, and d 1 is an integer of 1 to 10, w is an integer of 0 to 3, Rb is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkoxy group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxy group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group or C1-6 is an alkyl group, and Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 alkylaminosulfonyl group) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 11 is C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more substituents independently selected from the following), or a group selected from the formulas (XIII-1) to (XIII-11): Substituent group V a means a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, P 11 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 11 is -P(=O)(OH)-, q11 is an integer between 1 and 10, and q 12 is an integer between 1 and 20, and q 11 and q 12 When at least one of these is 2 or more, V 11 are the same or different} 5. The single-stranded oligonucleotide according to any one of 1. to 4., wherein the group is represented by the formula:

[0018] 6. The linking groups containing a non-nucleotide structure each independently have the following formula: [ka] {where, V 0 teeth, C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more independently selected substituents from The following formulas (X-1) to (X-9): [ka] (wherein o is an integer from 0 to 30, and p is an integer from 0 to 30). a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 0 is C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more independently selected substituents from is a group selected from the formulas (X-1) to (X-9), Substituent group V ameans a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, q1 is an integer of 1 to 10, q2 is an integer of 1 to 20, and when at least one of q1 and q2 is 2 or more, V 0 The single-stranded oligonucleotide according to any one of 1. to 5., wherein the aryl group is a group represented by the formula {wherein aryl is the same or different}.

[0019] 7. The single-stranded oligonucleotide according to any one of 1. to 6., wherein the first nucleotide sequence is an antisense sequence.

[0020] 8. The single-stranded oligonucleotide according to any one of 1. to 7., wherein X comprises at least one sugar-modified nucleotide and the first nucleotide sequence comprises at least four consecutive nucleotides that are recognized by RNase H.

[0021] 9. A single-stranded oligonucleotide described in any one of 1. to 8., wherein the first nucleotide sequence portion contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides.

[0022] 10. A single-stranded oligonucleotide described in any one of 1. to 9., wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to at least one of the 5' and 3' sides of the first nucleotide sequence portion.

[0023] 11. The single-stranded oligonucleotide according to any one of 1. to 10., wherein the first oligonucleotide comprises a phosphorothioate linkage.

[0024] 12. A single-stranded oligonucleotide according to any one of 1. to 11., wherein the first nucleotide sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

[0025] 13. The single-stranded oligonucleotide according to any one of 1. to 12., wherein the second nucleotide sequence is a sequence containing at least four consecutive nucleotides that are cleaved by RNase H.

[0026] 14. A single-stranded oligonucleotide described in any one of 1. to 13., wherein the second oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the second nucleotide sequence portion.

[0027] 15. The single-stranded oligonucleotide according to any one of 1. to 14., wherein m is 0, n is 0, and L is a linking group containing a non-nucleotide structure.

[0028] 16. A single-stranded oligonucleotide according to any one of 1. to 14., wherein n is 1, Yz comprises at least one sugar-modified nucleotide, and the nucleotide sequence Yz comprises an antisense sequence.

[0029] 17. The single-stranded oligonucleotide according to 16, wherein the antisense sequence contained in the nucleotide sequence Yz is a sequence containing at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA.

[0030] 18. The single-stranded oligonucleotide according to 16, wherein the antisense sequence portion contained in Yz contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides.

[0031] 19. A single-stranded oligonucleotide described in any one of 16 to 18, wherein the fourth oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the antisense sequence portion contained in Yz.

[0032] 20. The single-stranded oligonucleotide according to any one of 16. to 19., wherein the fourth oligonucleotide comprises at least four consecutive nucleotides that are cleaved by RNase H.

[0033] 21. The single-stranded oligonucleotide according to any one of 16. to 20., wherein L is a linking group containing a non-nucleotide structure, and Y and Yz are linked by a phosphodiester bond. 22. L has the following formula: [ka] (In the formula, W 5 is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), 21. The single-stranded oligonucleotide according to any one of 16. to 20., wherein Ly is a linking group comprising a non-nucleotide structure. 23. The single-stranded oligonucleotide according to any one of 16. to 20., wherein L and Ly are each independently a linking group containing a non-nucleotide structure.

[0034] 24. The single-stranded oligonucleotide according to any one of 16. to 23., wherein m is 0.

[0035] 25. A single-stranded oligonucleotide according to any one of 1. to 14. and 16. to 23., wherein m is 1 and Xz contains at least one ribonucleotide. 26. A single-stranded oligonucleotide according to any one of 1. to 14., 16. to 23. and 25., wherein m is 1 and Xz contains at least four consecutive nucleotides that are cleaved by RNase H. 27. A single-stranded oligonucleotide according to any one of 1. to 14. and 16. to 23., wherein m is 1, Xz comprises at least one sugar-modified nucleotide, and the nucleotide sequence Xz comprises an antisense sequence.

[0036] 28. A single-stranded oligonucleotide described in any one of 1. to 27., further comprising a group derived from a functional molecule having at least one function selected from the group consisting of a labeling function, a purification function, and a delivery function to a target site.

[0037] 29. The single-stranded oligonucleotide according to 28, wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides, proteins, and derivatives thereof.

[0038] 30. The single-stranded oligonucleotide according to 28. or 29., wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol, and tocotrienol.

[0039] 31. The single-stranded oligonucleotide according to 28. or 29., wherein the functional molecule is a sugar derivative that interacts with the asialoglycoprotein receptor.

[0040] 32. The single-stranded oligonucleotide according to 28. or 29., wherein the functional molecule is a peptide or protein selected from the group consisting of receptor ligands and antibodies.

[0041] 33. A pharmaceutical composition comprising the single-stranded oligonucleotide according to any one of 1. to 32. and a pharmacologically acceptable carrier.

[0042] 34. A method for regulating the function of a target RNA, comprising the step of contacting a cell with the single-stranded oligonucleotide according to any one of 1. to 32.

[0043] 35. A method for regulating the function of a target RNA in a mammal, comprising administering to the mammal a pharmaceutical composition comprising the single-stranded oligonucleotide described in any one of 1. to 32.

[0044] 36. A method for controlling expression of a target gene, comprising the step of contacting a cell with the single-stranded oligonucleotide described in any one of 1. to 32.

[0045] 37. A method for controlling expression of a target gene in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising the single-stranded oligonucleotide described in any one of 1. to 32.

[0046] 38. A method for producing a single-stranded oligonucleotide according to any one of 1. to 32., comprising a step of extending a nucleotide chain at the 3' end or 5' end of an oligonucleotide comprising at least one of X, L, and Y. [Effects of the Invention]

[0047] According to the present invention, it is possible to provide an oligonucleotide that can regulate the expression of a target gene with high efficiency, and also to provide an oligonucleotide that can be produced more easily than double-stranded oligonucleotides (e.g., HDO, HCDO).

[0048] The single-stranded oligonucleotide of the present invention is capable of effectively controlling the expression of a target gene by the antisense oligonucleotide that is its component, and is useful as a nucleic acid pharmaceutical. [Brief explanation of the drawings]

[0049] [Figure 1]FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 2] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 3] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 4] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 5] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 6] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 7] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 8] This is a conceptual diagram showing an embodiment of a single-stranded oligonucleotide according to this embodiment, in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 hybridize intramolecularly, and Yz containing an antisense sequence portion hybridizes intramolecularly with the third nucleotide sequence portion Xz2. [Figure 9]This is a conceptual diagram showing an embodiment of a single-stranded oligonucleotide according to this embodiment, in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 hybridize intramolecularly, and Yz containing an antisense sequence portion hybridizes intramolecularly with the third nucleotide sequence portion Xz2. [Figure 10] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 11] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 12] FIG. 1 is a conceptual diagram showing one embodiment in which X and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, intramolecularly hybridize. [Figure 13] FIG. 1 is a conceptual diagram showing one embodiment in which X and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, intramolecularly hybridize. [Figure 14] FIG. 1 is a conceptual diagram showing one embodiment in which X and the second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is an example of this embodiment, intramolecularly hybridize. [Figure 15] FIG. 1 is a conceptual diagram showing one embodiment in which X of a single-stranded oligonucleotide, which is an example of this embodiment, hybridizes intramolecularly with the second nucleotide sequence portion Y0. [Figure 16] FIG. 1 is a conceptual diagram showing one embodiment in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is an example of this embodiment, hybridize intramolecularly. [Figure 17] FIG. 1 is a conceptual diagram showing one embodiment in which X of a single-stranded oligonucleotide, which is an example of this embodiment, hybridizes intramolecularly with the second nucleotide sequence portion Y0. [Figure 18]1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in cells derived from human liver cancer. [Figure 19] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in cells derived from human liver cancer. [Figure 20] 1 is a graph showing the effect of oligonucleotides on the expression level of PTEN in human liver cancer-derived cells. [Figure 21] 1 is a graph showing the effect of oligonucleotides on the expression level of ApoB in human hepatoma-derived cells. [Figure 22] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in cells derived from human liver cancer. [Figure 23] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of ApoB in human hepatic cancer-derived cells. [Figure 24] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in cells derived from human liver cancer. [Figure 25] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of ApoB in human hepatic cancer-derived cells. [Figure 26] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. [Figure 27] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. [Figure 28] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. [Figure 29] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. [Figure 30]1 is a graph showing the effect on the ApoB expression level in the liver of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Figure 31] 1 is a graph showing the effect on the total cholesterol level in the plasma of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Figure 32] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in cells derived from human liver cancer. [Figure 33] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in cells derived from human liver cancer. [Figure 34] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of Aldolase A in human liver cancer-derived cells. [Figure 35] 1 is a graph showing the effect on the ApoB expression level in the liver of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Figure 36] 1 is a graph showing the effect on the total cholesterol level in the plasma of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Figure 37] 1 is a graph showing the effect of oligonucleotides on the expression level of PTEN in human liver cancer-derived cells. [Figure 38] 1 is a graph showing the effect on the ApoB expression level in the liver of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Figure 39] 1 is a graph showing the effect on the total cholesterol level in the plasma of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Figure 40] 1 is a graph showing the effect of administration of a single-stranded oligonucleotide according to this embodiment on the expression level of SRB1 in the liver of a C57BL / 6J mouse. DETAILED DESCRIPTION OF THE INVENTION

[0050] The terms used in this specification have the meanings commonly used in the relevant field unless otherwise specified. Each term used in this specification is explained below. In this specification, each term has the same meaning whether used alone or together with other terms, unless otherwise specified.

[0051] The term "antisense effect" refers to the control of the function of a target RNA by hybridizing a target RNA selected corresponding to a target gene with, for example, an oligonucleotide having a sequence complementary to a partial sequence of the target RNA. For example, when the target RNA is mRNA, this refers to the inhibition of translation of the target RNA by hybridization, the effect of converting a splicing function such as exon skipping, or the degradation of the target RNA upon recognition of the hybridized portion. Examples of oligonucleotides that produce the antisense effect include DNA and oligodeoxyribonucleotides, but oligonucleotides that produce the antisense effect are not limited to these and may also be RNA, oligoribonucleotides, or oligonucleotides designed to normally produce the antisense effect.

[0052] "Target RNA" refers to mRNA, mRNA precursor, or ncRNA, and includes mRNA transcribed from genomic DNA encoding the target gene, mRNA without base modifications, unspliced ​​mRNA precursor, and ncRNA. The "target RNA" whose function is controlled by the antisense effect is not particularly limited, and examples include RNA associated with genes whose expression is increased in various diseases. "Target RNA" may be any RNA synthesized by DNA-dependent RNA polymerase, and is preferably mRNA or mRNA precursor. More preferably, it is mammalian mRNA or mRNA precursor, and even more preferably, it is human mRNA or mRNA precursor.

[0053] "Hybridize" refers to the act of forming a double strand between oligonucleotides or groups derived from oligonucleotides containing complementary sequences, and the phenomenon in which oligonucleotides or groups derived from oligonucleotides containing complementary sequences form a double strand.

[0054] "Complementary" means that two nucleobases can form Watson-Crick base pairs (natural base pairs) or non-Watson-Crick base pairs (such as Hoogsteen base pairs) through hydrogen bonds. Two oligonucleotides or oligonucleotide-derived groups can "hybridize" if their sequences are complementary. Two oligonucleotides or oligonucleotide-derived groups do not need to be completely complementary to hybridize, but the degree of complementarity for two oligonucleotides or oligonucleotide-derived groups to hybridize is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, or 99% or more). Sequence complementarity can be determined using a computer program that automatically identifies subsequences of oligonucleotides. For example, OligoAnalyzer is one such software program provided by Integrated DNA Technologies. This program is also available on the website. Those skilled in the art can easily determine the conditions (temperature, salt concentration, etc.) under which two oligonucleotides or oligonucleotide-derived groups can hybridize. Furthermore, those skilled in the art can easily design antisense oligonucleotides complementary to a target RNA, for example, by using a BLAST program based on the nucleotide sequence of the target RNA. For details of the BLAST program, see Proceedings of the National Academy of Sciences of the United States of America (1990, Vol. 87, pp. 2264-68; 1993, Vol. 90, pp. 5873-77) and Journal of Molecular Biology (1990, Vol. 215, p. 403).

[0055] A "nucleotide" is a molecule that can be a building block of a nucleic acid (oligonucleotide), and typically has a base as a constituent element. A nucleotide is composed of, for example, a sugar, a base, and a phosphate. Nucleotides include ribonucleotides, deoxyribonucleotides, and sugar-modified nucleotides, which are described below.

[0056] "Oligonucleotide" refers to a molecule having a polymerized structure of one or more of the above nucleotides. When an "oligonucleotide" is composed of one nucleotide, the oligonucleotide can be referred to as a "nucleotide." The nucleotides contained in the "single-stranded oligonucleotide" molecule of the present invention are each independently linked to each other by a phosphodiester bond, a modified phosphodiester bond as described below, or a linking group containing a non-nucleotide structure as described below. The 3'-terminal nucleotide of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxy group or a phosphate group, more preferably a hydroxy group, and usually a hydroxy group, at its 3'-position. The 5'-terminal nucleotide of the single-stranded oligonucleotide molecule preferably has a hydroxy group or a phosphate group, more preferably a hydroxy group, and usually a hydroxy group, at its 5'-position.

[0057] The term "group derived from an oligonucleotide" refers to a group obtained by removing a hydrogen atom, hydroxy group, or the like from a hydroxy group at at least one of the 3'- and 5'-ends of the oligonucleotide, and is covalently linked to another group (e.g., a linking group, a group derived from another oligonucleotide, etc.) directly or indirectly via a phosphodiester bond or a modified phosphodiester bond. The hydroxy group at the 3'- or 5'-end includes the hydroxy group at the 3'- or 5'-position of the sugar moiety of a nucleotide, as well as a hydroxy group carried by a phosphate group (including modified phosphate groups such as thiophosphate groups). For example, a group obtained by removing a hydrogen atom from the hydroxy group at the 3'-end of an oligonucleotide and a group obtained by removing a hydroxy group from the phosphate group at the 5'-end of another oligonucleotide form a phosphodiester bond or a modified phosphodiester bond.

[0058] "Nucleotide sequence" means the base sequence of the nucleotides that make up an oligonucleotide. The term "nucleotide sequence portion" refers to a partial structure of a region of an oligonucleotide chain that has the nucleotide sequence.

[0059] In this specification, whether a "nucleotide sequence" contains or does not contain a nucleotide or an oligonucleotide chain has the same meaning as whether the corresponding "nucleotide sequence portion" contains or does not contain the nucleotide or the oligonucleotide chain. Furthermore, the "nucleotide sequence" has the same meaning as the base sequence of the "nucleotide sequence portion" that contains or does not contain the nucleotide or the oligonucleotide chain.

[0060] The term "sequence portion" refers to a partial structure of an oligonucleotide chain. For example, a sequence portion containing a nucleotide is a partial structure of a region of an oligonucleotide chain that contains the nucleotide. When a nucleotide sequence is a sequence selected from nucleotides, a sequence of consecutive nucleotides, etc., this has the same meaning as when the corresponding nucleotide sequence portion is a sequence portion selected from the nucleotides, a sequence portion of the nucleotides, etc.

[0061] "Deoxyribonucleotide" refers to a molecule of the above-mentioned "nucleotide" in which the sugar is 2'-deoxyribose, a base is bound to the carbon atom at the 1' position of 2'-deoxyribose, and a phosphate group is at the 3' or 5' position. The deoxyribonucleotide of the present invention may be a naturally occurring deoxyribonucleotide, or a deoxyribonucleotide in which the base moiety or the phosphodiester bond moiety of a naturally occurring deoxyribonucleotide has been modified. A single deoxyribonucleotide may be modified in a combination of multiple types at the base moiety or the phosphodiester bond site. The modified deoxyribonucleotides are described, for example, in Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), etc.

[0062] When the "deoxyribonucleotides" constitute the single-stranded oligonucleotide molecule of the present invention, the 3' position of the deoxyribonucleotide is usually linked to another nucleotide or linking group via a phosphodiester bond or a modified phosphodiester bond (e.g., a phosphorothioate bond), and the 5' position of the deoxyribonucleotide is linked to another nucleotide or linking group via a phosphodiester bond or a modified phosphodiester bond (e.g., a phosphorothioate bond). The deoxyribonucleotide at the 3' end of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxy group or a phosphate group at its 3' position, and the 5' position is as described above. The deoxyribonucleotide at the 5' end of the single-stranded oligonucleotide molecule preferably has a hydroxy group or a phosphate group at its 5' position, and the 3' position is as described above.

[0063] The term "oligodeoxyribonucleotide" refers to an oligonucleotide composed of the above-mentioned deoxyribonucleotides. The deoxyribonucleotides constituting the oligodeoxyribonucleotide may be the same or different.

[0064] "DNA" refers to an oligonucleotide composed of natural deoxyribonucleotides, which may be identical or different.

[0065] The term "deoxyribonucleoside group" refers to a group in which a base is bound to the carbon atom at the 1' position of 2'-deoxyribose and the hydroxy groups at the 3' and 5' positions of the 2'-deoxyribose have been removed. The base moiety in the deoxyribonucleoside group of the present invention may be a naturally occurring base or a modified naturally occurring base. Multiple types of modifications to the base moiety may be combined and applied to a single deoxyribonucleoside group. The modifications are described, for example, in Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), and Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365).

[0066] "Ribonucleotide" refers to a molecule of the aforementioned "nucleotide" in which the sugar is ribose, a base is bound to the 1' carbon atom of the ribose, and a phosphate group is located at the 3' or 5' position. The ribonucleotide of the present invention may be a naturally occurring ribonucleotide, or a naturally occurring ribonucleotide in which the base moiety or the phosphodiester linkage moiety has been modified. Multiple modifications of the base moiety or the phosphodiester linkage moiety may be combined in one ribonucleotide. The modified ribonucleotides are described, for example, in Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), and Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), among others.

[0067] When the "ribonucleotide" constitutes a single-stranded oligonucleotide molecule of the present invention, the 3' position of the ribonucleotide is typically linked to another nucleotide or linking group via a phosphodiester bond or a modified phosphodiester bond (e.g., a phosphorothioate bond), and the 5' position of the ribonucleotide is linked to another nucleotide or linking group via a phosphodiester bond or a modified phosphodiester bond (e.g., a phosphorothioate bond). The 3'-terminal ribonucleotide of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxy group or a phosphate group at its 3' position, and the 5'-position is as described above. The 5'-terminal ribonucleotide of the single-stranded oligonucleotide molecule preferably has a hydroxy group or a phosphate group at its 5' position, and the 3'-position is as described above.

[0068] The term "oligoribonucleotide" refers to an oligonucleotide composed of the above-mentioned ribonucleotides. The ribonucleotides constituting the oligoribonucleotide may be the same or different.

[0069] "RNA" refers to an oligonucleotide composed of natural ribonucleotides. The natural ribonucleotides that make up the RNA may be identical or different.

[0070] The term "ribonucleoside group" refers to a group in which a base is bound to the carbon atom at the 1' position of ribose and the hydroxy groups at the 3' and 5' positions of the ribose have been removed. The base moiety in the ribonucleoside group of the present invention may be a naturally occurring base or a modified naturally occurring base. A single ribonucleoside group may be modified with a combination of multiple types of base moieties. The modifications are described, for example, in Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), and Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365).

[0071] A "sugar-modified nucleotide" refers to a nucleotide in which the sugar moiety of the deoxyribonucleotide or ribonucleotide has been partially substituted with one or more substituents, or the entire sugar backbone has been replaced with a sugar backbone other than ribose and 2'-deoxyribose (e.g., a 5- or 6-membered sugar backbone such as hexitol or threose), or the entire sugar backbone or a ring portion of the sugar backbone has been replaced with a 5- to 7-membered saturated or unsaturated ring (e.g., cyclohexane, cyclohexene, morpholine, etc.) or a partial structure capable of forming a 5- to 7-membered ring through hydrogen bonding (e.g., a peptide structure), or the ring of the sugar moiety has been opened, or the open ring portion has been modified. The base moiety of a "sugar-modified nucleotide" may be a naturally occurring base or a modified base. Furthermore, the phosphodiester bond of a "sugar-modified nucleotide" may be a phosphodiester bond or a modified phosphodiester bond. Multiple types of modifications to the base moiety or the phosphodiester bond site may be combined in a single sugar-modified nucleotide. Modifications of the ring-opened moiety include, for example, halogenation, alkylation (for example, methylation, ethylation), hydroxylation, amination, thiolation, and the like, as well as demethylation.

[0072] The "sugar-modified nucleotide" may be a bridged nucleotide or a non-bridged nucleotide. Examples of sugar-modified nucleotides include nucleotides disclosed as being suitable for use in antisense methods in JP-A-10-304889, WO 2005 / 021570, WO 10-195098, JP-T-2002-521310, WO 2007 / 143315, WO 2008 / 043753, WO 2008 / 029619, and WO 2008 / 049085 (hereinafter, these documents are referred to as "documents related to antisense methods"). The above-mentioned document discloses nucleotides such as hexitol nucleotides (HNA), cyclohexene nucleotides (CeNA), peptide nucleic acids (PNA), glycol nucleic acids (GNA), threonucleotides (TNA), morpholino nucleic acids, tricyclo-DNA (tcDNA), 2'-O-methylated nucleotides, 2'-MOE (2'-O-methoxyethyl)-substituted nucleotides, 2'-AP (2'-O-aminopropyl)-substituted nucleotides, 2'-fluoro-substituted nucleotides, 2'-F-arabinonucleotides (2'-F-ANA), bridged nucleotides (BNA (Bridged Nucleic Acid)), and 2'-O-methylcarbamoylethylated nucleotides (MCE). Sugar-modified nucleotides are also disclosed in the Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), etc.

[0073] When the "sugar-modified nucleotide" constitutes a single-stranded oligonucleotide molecule of the present invention, for example, the 3' position of the sugar-modified nucleotide is linked to another nucleotide or a linking group via a phosphodiester bond or a modified phosphodiester bond (e.g., a phosphorothioate bond), and the 5' position of the sugar-modified nucleotide is linked to another nucleotide or a linking group via a phosphodiester bond or a modified phosphodiester bond (e.g., a phosphorothioate bond). The sugar-modified nucleotide at the 3' end of a single-stranded oligonucleotide molecule of the present invention preferably has a hydroxy group or a phosphate group at its 3' position, and the 5' position is as described above. The sugar-modified nucleotide at the 5' end of a single-stranded oligonucleotide molecule preferably has a hydroxy group or a phosphate group at its 5' position, and the 3' position is as described above.

[0074] The base moiety in the deoxyribonucleotides, ribonucleotides and sugar-modified nucleotides is preferably at least one selected from the group consisting of adenine (A), guanine (G), thymine (T), cytosine (C), uracil (U) and 5-methylcytosine (5-me-C).

[0075] Examples of modifications of the base moiety in deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides include halogenation, methylation, ethylation, n-propylation, isopropylation, cyclopropylation, n-butylation, isobutylation, s-butylation, t-butylation, cyclobutylation, hydroxylation, amination, thiolation, demethylation, etc. More specific examples include 5-methylation, 5-fluorolation, 5-bromination, 5-iodination, and N4-methylation of cytosine; 2-thiolation, 5-demethylation, 5-fluorolation, 5-bromination, and 5-iodination of thymine; 2-thiolation, 5-fluorolation, 5-bromination, and 5-iodination of uracil; N6-methylation and 8-bromination of adenine; and N2-methylation and 8-bromination of guanine. In addition, examples of modifications of the base moiety in nucleotides are disclosed in the Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), etc., and these can be used for the base moiety in deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides.

[0076] Examples of modifications of the phosphodiester bond (phosphate moiety) in deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides include phosphorothioation, methylphosphonate (including chiral-methylphosphonate), methylthiophosphonate, phosphorodithioate, phosphoroamidate, phosphorodiamidate, phosphoroamidothioate, and boranophosphate. Furthermore, examples of modifications of the phosphodiester bond moiety in nucleotides are disclosed in the Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), etc., and these can be used for the phosphodiester bond moiety in deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides.

[0077] Examples of modifications in which the sugar moiety of a deoxyribonucleotide or ribonucleotide is partially substituted with a single substituent include 2'-O-methylation, 2'-O-methoxyethylation (MOE), 2'-O-aminopropylation (AP), 2'-fluoro, and 2'-O-{(N-methylcarbamoyl)ethyl}ation (MCE).

[0078] A "bridged nucleotide" is a sugar-modified nucleotide in which the bridge unit is substituted by two substitutions in the sugar moiety, and examples thereof include nucleotides in which the 2'- and 4'-positions are bridged.

[0079] The 2'- and 4'-bridged nucleotide (2',4'-BNA) may be any nucleotide having a sugar moiety in which the carbon atom at the 2' position and the carbon atom at the 4' position are bridged by two or more atoms, such as C 2-6an alkylene group (the alkylene group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, an oxo group, and a thioxo group, and one or two methylene groups of the alkylene group are unsubstituted or independently substituted with -O-, -NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 and -S-, which represents an alkyl group) and a group selected from the group consisting of -S-. By combining the above substitutions, the group bridging the 2'-position and the 4'-position of 2',4'-BNA is -C(=O)-O-, -OC(=O)-NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 (representing an alkyl group), -C(=O)-NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 (representing an alkyl group), -C(=S)-NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 In this case, the alkyl group may contain a group represented by -C(=S)-NR 1 -containing sugar-modified nucleotides are -C(=O)-NR 1 The nucleotide can be synthesized from a sugar-modified nucleotide containing - or an intermediate thereof using a thiocarbonylation reagent (for example, Lawesson's reagent) and carrying out a protection reaction and a deprotection reaction as necessary.

[0080] Examples of such BNAs include Locked Nucleic Acid (registered trademark), also known as LNA, α-L-methyleneoxy (4'-CH2-O-2') BNA or β-D-methyleneoxy (4'-CH2-O-2') BNA, ethyleneoxy (4'-(CH2)2-O-2') BNA, also known as ENA, β-D-thio (4'-CH2-S-2') BNA, aminooxy (4'-CH2-ON(R11 )-2')BNA(R 11 is H or CH3), 2',4'-BNA NC Also called oxyamino (4'-CH2-N(R 12 )-O-2')BNA(R 12 is H or CH3), 2',4'-BNA COC , 3'-amino-2',4'-BNA, 5'-methyl BNA, (4'-CH(CH3)-O-2') BNA, also called cEt-BNA, (4'-CH(CHOCH3)-O-2') BNA, also called cMOE-BNA, amide type BNA (4'-C(=O)-N(R 13 )-2')BNA(R 13 is H or CH3), other BNAs known to those skilled in the art, etc.

[0081] "A nucleotide in which at least one of the sugar moiety, base moiety, and phosphate moiety is modified" means a deoxyribonucleotide in which at least one of the base moiety and phosphate moiety of a naturally occurring deoxyribonucleotide is modified, a ribonucleotide in which at least one of the base moiety and phosphate moiety of a naturally occurring ribonucleotide is modified, or a sugar moiety-modified nucleotide.

[0082] "n-" means normal, "s-" means secondary, "i-" means iso, and "t-" means tertiary.

[0083] "Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

[0084] "C 1-6 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl groups. In this specification, "Me" means methyl, "Et" means ethyl, and "Pr" means propyl.

[0085] "Haro C 1-6 The "C alkyl group" refers to the "C 1-6 The term "alkyl group" refers to a group in which a hydrogen atom at any position of the "alkyl group" is substituted with one or more of the above-mentioned "halogen atoms."

[0086] "C 1-6 The term "alkylene group" refers to a divalent group obtained by removing one hydrogen atom from any position of a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene (ethanediyl) group, a propane-1,3-diyl group, a propane-2,2-diyl group, a 2,2-dimethyl-propane-1,3-diyl group, a hexane-1,6-diyl group, and a 3-methylbutane-1,2-diyl group. "C 2-6 The "alkylene group" refers to the "C 1-6 Among the "alkylene groups," "a straight-chain or branched divalent group having 2 to 6 carbon atoms" means a straight-chain or branched divalent group having 2 to 6 carbon atoms, and examples thereof include the above-mentioned "C 1-6 The same applies to the "alkylene group." "C 2-20 The term "alkylene group" refers to a divalent group obtained by removing one hydrogen atom from any position of a linear or branched saturated hydrocarbon group having 2 to 20 carbon atoms. 8-12 The term "alkylene group" means a divalent group obtained by removing one hydrogen atom at any position from a linear or branched saturated hydrocarbon group having 8 to 12 carbon atoms. 2-50 The term "alkylene group" refers to a divalent group formed by removing one hydrogen atom at any position from a linear or branched saturated hydrocarbon group having 2 to 50 carbon atoms.

[0087] "C 2-20 The term "alkenylene group" refers to a divalent group formed by removing one hydrogen atom at any position from a straight-chain or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms and containing at least one double bond.

[0088] "C 1-6 The "alkoxy group" refers to the "C 1-6It means a group in which an "alkyl group" is bonded to an oxy group, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, an n-pentyloxy group, an isopentyloxy group, a neopentyloxy group, an n-hexyloxy group, and an isohexyloxy group.

[0089] "Mono C 1-6 The "C alkylamino group" is a group defined as one of the "C 1-6 "Alkyl group" means a group in which an "alkyl group" is bonded to an amino group, and examples thereof include methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, s-butylamino group, t-butylamino group, n-pentylamino group, isopentylamino group, neopentylamino group, n-hexylamino group, and isohexylamino group.

[0090] "The C 1-6 The term "alkylamino group" refers to a group consisting of two identical or different "C 1-6 "Alkyl group" means a group bonded to an amino group, and includes, for example, dimethylamino group, diethylamino group, di-n-propylamino group, diisopropylamino group, di-n-butylamino group, di-n-pentylamino group, di-n-hexylamino group, N-methyl-N-ethylamino group, and N-methyl-N-isopropylamino group.

[0091] "C 1-6 Alkylcarbonyl group, HaloC 1-6 alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, Mono C 1-6 Alkylaminocarbonyl group" and "diC 1-6 The "C alkylaminocarbonyl group" is 1-6 Alkyl group, Halo C 1-6 alkyl group," "C 1-6 Alkoxy group, Mono C 1-6 Alkylamino group" and "diC 1-6 An "alkylamino group" refers to a group attached to a carbonyl group (-C(O)-).

[0092] "C 1-6 Alkyl sulfonyl group, halo C 1-6 alkylsulfonyl group," "C 1-6 Alkoxysulfonyl group, Mono C 1-6 Alkylaminosulfonyl group" and "diC 1-6 The "C alkylaminosulfonyl group" is defined as 1-6 Alkyl group, Halo C 1-6 alkyl group," "C 1-6 Alkoxy group, Mono C 1-6 Alkylamino group" and "diC 1-6 An "alkylamino group" refers to a group bonded to a sulfonyl group (-S(O)2-).

[0093] The term "oxo group" refers to a group in which an oxygen atom is substituted via a double bond (=O). When an oxo group is substituted for a carbon atom, it combines with the carbon atom to form a carbonyl group.

[0094] The term "thioxo group" refers to a group in which a sulfur atom is substituted via a double bond (=S). When a thioxo group is substituted for a carbon atom, it combines with the carbon atom to form a thiocarbonyl group.

[0095] Sugar-modified nucleotides are not limited to those exemplified herein. Numerous sugar-modified nucleotides are known in the art, and sugar-modified nucleotides described in, for example, U.S. Patent No. 8,299,039 by Tachas et al. (especially columns 17 to 22), or in Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471), Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), etc., can also be used in embodiments of the present invention.

[0096] Those skilled in the art can select and use an appropriate sugar-modified nucleotide from among such sugar-modified nucleotides, taking into consideration factors such as antisense effect, affinity for a partial sequence of the target RNA, and resistance to nucleases.

[0097] "RNase H" is generally known as a ribonuclease that recognizes a double-stranded structure formed by hybridizing DNA and RNA and cleaves the RNA to produce single-stranded DNA. RNase H is not limited to double-stranded structures formed by hybridizing DNA and RNA, but can also recognize double-stranded structures in which at least one of the base moiety, phosphodiester bond moiety, and sugar moiety of at least one of the DNA and RNA is modified. For example, it can also recognize a double-stranded structure formed by hybridizing an oligodeoxyribonucleotide and an oligoribonucleotide. Therefore, when DNA hybridizes with RNA, it can be recognized by RNase H. The same applies when at least one of the base moiety, phosphodiester bond moiety, and sugar moiety is modified in at least one of the DNA and RNA. A typical example is an oligonucleotide in which the phosphodiester bond moiety of the DNA is modified to phosphorothioate. When hybridized with DNA, RNA can be cleaved by RNase H. The same applies when at least one of the base moiety, phosphodiester bond moiety, and sugar moiety of at least one of the DNA and RNA is modified. Examples of DNA and / or RNA modifications that can be recognized by RNase H are described, for example, in Nucleic Acids Research (2014, Vol. 42, No. 8, pp. 5378-89), Bioorganic and Medicinal Chemistry Letters (2008, Vol. 18, pp. 2296-2300), Molecular Biosystems (2009, Vol. 5, pp. 838-843), Nucleic Acid Therapeutics (2015, Vol. 25, No. 5, pp. 266-274), and The Journal of Biological Chemistry (2004, Vol. 279, No. 35, pp. 36317-36326). The RNase H used in the present invention is preferably mammalian RNase H, more preferably human RNase H, and particularly preferably human RNase H1.

[0098] The phrase "at least four consecutive nucleotides recognized by RNase H" includes four or more consecutive nucleotides and is not particularly limited as long as they are recognized by RNase H. However, the consecutive nucleotides are preferably independently selected from deoxyribonucleotides and sugar-modified nucleotides, more preferably independently selected from deoxyribonucleotides. The consecutive nucleotides may be the same or different.

[0099] The term "at least four consecutive nucleotides cleaved by RNase H" includes four consecutive nucleotides, and is not particularly limited as long as they are cleaved by RNase H, but includes at least one ribonucleotide. Furthermore, it is preferable that they include oligoribonucleotides, and more preferably RNA. It is more preferable that the consecutive nucleotides are independently selected from ribonucleotides. It is more preferable that the consecutive nucleotides are linked to each other by phosphodiester bonds. The consecutive nucleotides may be the same or different.

[0100] Next, the antisense sequence, the antisense sequence portion, and the nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence in the present invention will be explained.

[0101] "Antisense sequence" refers to a base sequence of nucleotides constituting an oligonucleotide that allows hybridization with a target RNA.

[0102] The term "antisense sequence portion" refers to the partial structure of the region of the oligonucleotide strand that has the antisense sequence.

[0103] In this specification, whether an "antisense sequence" contains or does not contain a nucleotide or an oligonucleotide chain has the same meaning as whether the corresponding "antisense sequence portion" contains or does not contain the nucleotide or the oligonucleotide chain. Furthermore, the "antisense sequence" has the same meaning as the base sequence of the "antisense sequence portion" that contains or does not contain the nucleotide or the oligonucleotide chain.

[0104] The antisense sequence portion does not need to hybridize with the entire target RNA, but only needs to hybridize with at least a portion of the target RNA, and usually hybridizes with at least a portion of the target RNA. For example, the expression of the target gene is controlled by hybridizing at least a portion of the target RNA with an oligonucleotide (such as DNA, oligodeoxyribonucleotide, or an oligonucleotide designed to produce an antisense effect) having an antisense sequence complementary to a partial sequence of the target RNA. Furthermore, the entire antisense sequence portion does not need to hybridize, and only a portion of the antisense sequence may not hybridize, but it is preferable that the entire antisense sequence portion hybridizes.

[0105] The complementarity between the antisense sequence and a partial sequence of the target RNA is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, 99% or more). In order for the antisense sequence portion and at least a portion of the target RNA to hybridize, their sequences do not need to be completely complementary, but completely complementary is even more preferable.

[0106] The antisense sequence is preferably a sequence containing "at least four consecutive nucleotides that are recognized by RNase H when hybridized with the target RNA" or a sequence containing "at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides."

[0107] Those skilled in the art can easily determine a nucleotide sequence that matches an antisense sequence that "is capable of hybridizing with a target RNA" by using a BLAST program, etc. The same applies to a nucleotide sequence that matches "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA."

[0108] The "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA" is usually 4 to 30 consecutive nucleotides, preferably 4 to 20 consecutive nucleotides, more preferably 5 to 16 consecutive nucleotides, even more preferably 6 to 12 consecutive nucleotides, and particularly preferably 8 to 10 consecutive nucleotides. The consecutive nucleotides are preferably independently selected from deoxyribonucleotides and sugar-modified nucleotides, more preferably independently selected from deoxyribonucleotides. 8 to 10 consecutive deoxyribonucleotides are particularly preferred. The consecutive nucleotides may be the same or different from each other.

[0109] Furthermore, from the viewpoint of excellent pharmacokinetics, it is preferable that at least one nucleotide of the consecutive nucleotides is phosphorothioated.It is more preferable that at least one of the 3'-terminal and 5'-terminal nucleotides of the consecutive nucleotides is phosphorothioated, and it is even more preferable that both the 3'-terminal and 5'-terminal nucleotides are phosphorothioated.It is even more preferable that 80% of the consecutive nucleotides are phosphorothioated, and even more preferable that 90% of the nucleotides are phosphorothioated.It is particularly preferable that all of the consecutive nucleotides are phosphorothioated.

[0110] When the antisense sequence contains "at least four consecutive nucleotides recognized by RNase H upon hybridization with a target RNA," from the viewpoint of increasing affinity for a partial sequence of the target RNA or resistance to nucleases, it is preferable that 1 to 10 sugar-modified nucleotides be linked adjacent to at least one of the 3' and 5' ends of the "at least four consecutive nucleotides recognized by RNase H upon hybridization with a target RNA" (antisense sequence portion), more preferably 1 to 7 sugar-modified nucleotides be linked adjacent to at least one of the 3' and 5' ends, even more preferably 2 to 5 sugar-modified nucleotides be linked adjacent to at least one of the 3' and 5' ends, and even more preferably 2 to 3 sugar-modified nucleotides be linked adjacent to at least one of the 3' and 5' ends. Here, one or more deoxyribonucleotides or ribonucleotides, or both, may be contained between the multiple sugar-modified nucleotides on at least one of the 3' and 5' ends, but it is preferable that the multiple sugar-modified nucleotides be contiguous. Furthermore, the one or more sugar-modified nucleotides are preferably bound adjacently to both the 3'-side and the 5'-side of the antisense sequence portion. When multiple sugar-modified nucleotides are bound adjacently to at least one of the 3'-side and the 5'-side of the antisense sequence portion, "multiple sugar-modified nucleotides are bound adjacently" means that the multiple sugar-modified nucleotides and the oligonucleotide chains composed of deoxyribonucleotides and ribonucleotides contained between the multiple sugar-modified nucleotides are bound adjacently. When multiple sugar-modified nucleotides are bound adjacently to at least one of the 3'-side and the 5'-side, the respective sugar-modified nucleotides may be the same or different.

[0111] The sugar-modified nucleotide moiety attached adjacent to at least one of the 3' and 5' ends of the "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA" may or may not hybridize to the target RNA, but it is preferable that it hybridizes to the target RNA from the same viewpoint as above.

[0112] Furthermore, from the viewpoint of excellent in vivo kinetics, it is preferable that at least one of the sugar-modified nucleotides located on the 3'-side and 5'-side of the "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA" is phosphorothioated, more preferably that at least one of the sugar-modified nucleotides located on the 3'-side and at least one of the sugar-modified nucleotides located on the 5'-side is phosphorothioated, even more preferably that 50% is phosphorothioated, and even more preferably that 80% is phosphorothioated. Furthermore, it is preferable that all are phosphorothioated. When multiple sugar-modified nucleotides are located on the 3'-side, the bond between the nucleotides is preferably phosphorothioated, and the same applies when multiple sugar-modified nucleotides are located on the 5'-side.

[0113] At least a portion of the "at least four consecutive nucleotides recognized by RNase H when hybridized to the target RNA" may hybridize within the molecule, and a portion may not hybridize, but it is preferable that the entirety hybridize. The sugar-modified nucleotides attached adjacent to at least one of the 3' and 5' sides of the "at least four consecutive nucleotides recognized by RNase H when hybridized to the target RNA" may or may not hybridize within the molecule.

[0114] When the antisense sequence is a sequence "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," the antisense sequence portion (mixmer) may or may not contain ribonucleotides or deoxyribonucleotides, but it may contain at least one sugar-modified nucleotide and not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. The antisense sequence portion is preferably a partial structure of an oligonucleotide consisting of nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides, and the sugar-modified nucleotide content is, for example, 25% or more. From the viewpoint of increasing affinity for a partial sequence of a target RNA or resistance to nucleases, the sugar-modified nucleotide content is preferably 30% or more, more preferably 50% or more. From the same viewpoint, it is preferable that at least one of the 3'- and 5'-terminal nucleotides of this antisense sequence portion is a sugar-modified nucleotide, and it is more preferable that the 3'- and 5'-terminal nucleotides are sugar-modified nucleotides. In another embodiment, the content of sugar-modified nucleotides in the antisense sequence portion is preferably 40 to 70%, more preferably 50 to 60%. In another embodiment, the content of sugar-modified nucleotides in the antisense sequence portion is preferably 100%.

[0115] It is more preferable that the antisense sequence portion "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" does not contain an oligonucleotide chain consisting of three consecutive deoxyribonucleotides.

[0116] The antisense sequence portion (mixmer) "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" is generally 4 to 30 consecutive nucleotides, preferably 8 to 25 consecutive nucleotides, more preferably 10 to 20 consecutive nucleotides, and even more preferably 14 to 16 consecutive nucleotides. These consecutive nucleotides may be the same or different.

[0117] Furthermore, from the viewpoint of excellent pharmacokinetics, it is preferable that at least one nucleotide of the nucleotides constituting the antisense sequence portion (mixmer) "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" is phosphorothioated. It is more preferable that at least one of the 3'- and 5'-terminal nucleotides of the antisense sequence portion is phosphorothioated. It is even more preferable that 80% of the bonds between nucleotides contained in the antisense sequence portion are phosphorothioated, even more preferably 90% are phosphorothioated, and it is particularly preferable that all are phosphorothioated.

[0118] At least a portion of the antisense sequence portion (mixmer) "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" may or may not hybridize intramolecularly. In a single-stranded oligonucleotide molecule in which the antisense sequence portion (mixmer) does not hybridize intramolecularly, for example, the antisense sequence portion is present in the order of the antisense sequence portion (mixmer), Lx, first nucleotide sequence portion, L, and second nucleotide sequence portion, and the number of nucleotides contained in Y (and Yz, Ly) is set so that the antisense sequence portion does not hybridize intramolecularly; or the antisense sequence portion is present in the order of the first nucleotide sequence portion, L, second nucleotide sequence portion, Ly, and the antisense sequence portion (mixmer), and the number of nucleotides contained in X (and Xz, Lx) is set so that the antisense sequence portion does not hybridize intramolecularly.

[0119] Although it is not necessary for 1 to 10 sugar-modified nucleotides to be bound adjacent to at least one of the 3' and 5' ends of the antisense sequence portion "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," they may be bound. In this case, the one or more sugar-modified nucleotides may or may not hybridize intramolecularly, as in the case of the sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA."

[0120] The "sugar-modified nucleotide" contained in the antisense sequence portion may be a nucleotide that has increased affinity for a partial sequence of a target RNA or increased resistance to nucleases due to substitution or the like, but is preferably a 2'-O-methylated nucleotide, a 2'-O-methoxyethyl (2'-MOE)-modified nucleotide, a 2'-O-aminopropyl (2'-AP)-modified nucleotide, a 2'-fluoro-modified nucleotide, a 2'-F-arabinonucleotide (2'-F-ANA), a bridged nucleotide (BNA (Bridged Nucleic Acid)), or a 2'-O-methylcarbamoylethyl (2'-MCE)-modified nucleotide, more preferably a BNA, a 2'-O-methylated nucleotide, a 2'-MOE-modified nucleotide, or a 2'-MCE-modified nucleotide, even more preferably a BNA or a 2'-O-methylated nucleotide, still more preferably an LNA containing a partial structure represented by the following formula (II) or a 2'-O-methylated nucleotide, and particularly preferably an LNA. The same applies to one or more sugar-modified nucleotides attached adjacent to the 3' side of the antisense sequence portion and one or more sugar-modified nucleotides attached adjacent to the 5' side of the antisense sequence portion.

[0121] [ka]

[0122] In the formula, Base represents a base moiety and is a purin-9-yl group or a 2-oxo-pyrimidin-1-yl group, and the purin-9-yl group and the 2-oxo-pyrimidin-1-yl group are unmodified or modified. Here, the 2-oxo-pyrimidin-1-yl group has the same meaning as the 2-oxo-1H-pyrimidin-1-yl group. The purin-9-yl group and the 2-oxo-pyrimidin-1-yl group also include their respective tautomers.

[0123] The types, numbers, and positions of sugar-modified nucleotides, deoxyribonucleotides, and ribonucleotides in the antisense sequence portion can affect the antisense effect, etc., of the single-stranded oligonucleotides disclosed herein. The types, numbers, and positions vary depending on the sequence of the target RNA, etc., and therefore cannot be generalized. However, those skilled in the art can determine a preferred embodiment by taking into consideration the descriptions in literature related to the antisense method. Furthermore, the antisense effect of a single-stranded oligonucleotide after modification of the base moiety, sugar moiety, or phosphodiester bond moiety can be measured, and if the measured value is not significantly lower than that of the single-stranded oligonucleotide before modification (for example, if the measured value of the modified single-stranded oligonucleotide is 30% or more of the measured value of the single-stranded oligonucleotide before modification), the modification can be evaluated as a preferred embodiment. The antisense effect can be measured, for example, as shown in the Examples below, by introducing a test oligonucleotide into cells or the like, and measuring the expression level of the target RNA, the expression level of cDNA associated with the target RNA, the amount of protein associated with the target RNA, etc., controlled by the antisense effect of the test oligonucleotide, appropriately using known techniques such as Northern blotting, quantitative PCR, Western blotting, etc. The same applies to one or more sugar-modified nucleotides bound adjacent to the 3' side of the antisense sequence portion, the deoxyribonucleotides and ribonucleotides contained between the multiple sugar-modified nucleotides, the one or more sugar-modified nucleotides bound adjacent to the 5' side of the antisense sequence portion, and the deoxyribonucleotides and ribonucleotides contained between the multiple sugar-modified nucleotides.

[0124] In an antisense sequence portion "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," at least two nucleotides on either the 3' or 5' side are preferably sugar-modified nucleotides, and the sugar-modified nucleotides are preferably bridged nucleotides, particularly preferably LNA. When the two nucleotides on the 3' side of the antisense sequence portion are sugar-modified nucleotides, two or more of the three nucleotides on the 5' side are preferably sugar-modified nucleotides, linked in order from the terminal of the antisense sequence portion in one of the following orders: When the two nucleotides on the 5' side of the antisense sequence portion are sugar-modified nucleotides, two or more of the three nucleotides on the 3' side are sugar-modified nucleotides, linked in order from the terminal of the antisense sequence portion in one of the following orders: In these orders, the left side is the terminal side of the antisense sequence portion, and the right side is the interior of the antisense sequence portion. The sugar-modified nucleotides are preferably bridged nucleotides, particularly preferably LNA. Sugar-modified nucleotides - Sugar-modified nucleotides - Sugar-modified nucleotides Sugar-modified nucleotides - sugar-modified nucleotides - deoxyribonucleotides Sugar-modified nucleotides - Deoxyribonucleotides - Sugar-modified nucleotides

[0125] When a single-stranded oligonucleotide contains a nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion, the type, number, and position of modification of sugar-modified nucleotides, deoxyribonucleotides, and ribonucleotides in the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" may affect the antisense effect of the single-stranded oligonucleotide. The preferred embodiment varies depending on the type and sequence of the nucleotide to be modified, and therefore cannot be generalized. However, as with the antisense sequence portion described above, it can be determined by measuring the antisense effect of the single-stranded oligonucleotide after modification. From the viewpoint that the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" is degraded by nucleases such as RNase H in specific cells to generate an oligonucleotide containing the antisense sequence portion and thereby easily exert its antisense effect, the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" preferably contains "at least four consecutive nucleotides that can be cleaved by RNase H," and preferably contains at least one ribonucleotide. Furthermore, it preferably contains an oligoribonucleotide, and more preferably contains RNA. More preferably, the consecutive nucleotides are independently selected from ribonucleotides, and more preferably, the consecutive nucleotides are linked to each other by phosphodiester bonds. The consecutive nucleotides may be identical or different.

[0126] The complementarity between the antisense sequence portion and the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, or 99% or more). For hybridization between the antisense sequence portion and the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion," their sequences do not need to be completely complementary, but they may be completely complementary. Furthermore, the entire "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" does not need to hybridize to the antisense sequence portion; a portion may not hybridize, but the entire portion may hybridize. The "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" may partially hybridize with the antisense sequence portion, and the number of partially hybridizing nucleotides is usually selected depending on other factors such as the stability of the intramolecularly hybridized structure, the strength of the antisense effect on the target RNA, cost, synthesis yield, etc.

[0127] Next, the single-stranded oligonucleotide molecule of the present invention will be described. The single-stranded oligonucleotide of the present invention comprises X, Y, and L. In an embodiment of the single-stranded oligonucleotide of the present invention, An embodiment in which neither Xz nor Lx, nor Yz nor Ly is contained (in the formula (I), m is 0 and n is 0); an embodiment in which Xz and Lx are not included and Yz and Ly are included (in the formula (I) above, m is 0 and n is 1); An embodiment containing Xz and Lx but not containing Yz and Ly (in the formula (I), m is 1 and n is 0); Examples include an embodiment containing both Xz and Lx, and both Yz and Ly (wherein m is 1 and n is 1 in the formula (I) above).

[0128] X, Y, Xz, and Yz in the present invention will be explained below. There are several embodiments of the present invention, but first, common points will be explained.

[0129] X is a group derived from a first oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and the deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides are each independently unmodified or modified at least one of the base moiety and the phosphate moiety. The first oligonucleotide contains at least one nucleotide modified at at least one of the sugar moiety, the base moiety, and the phosphate moiety. The first oligonucleotide has a nucleotide sequence X, and the nucleotide sequence X contains a first nucleotide sequence that allows hybridization with at least a portion of the second oligonucleotide.

[0130] Nucleotide sequence X is a base sequence of nucleotides constituting the first oligonucleotide, and includes a first nucleotide sequence. The first nucleotide sequence is a base sequence of nucleotides constituting the first nucleotide sequence portion.

[0131] The number of nucleotides contained in X is 7 to 100, preferably 10 to 50, more preferably 10 to 35, even more preferably 12 to 25, still more preferably 13 to 20, and particularly preferably 13 to 14. The number of nucleotides contained in X is usually selected depending on other factors such as the strength of the antisense effect on the target RNA, the stability of the intramolecular hybridized structure, cost, and synthesis yield.

[0132] Y is a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and the deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides are each independently unmodified or modified at least at one of the base moiety and the phosphate moiety. The second oligonucleotide has a nucleotide sequence Y, which is capable of hybridizing with at least a portion of the first oligonucleotide and includes a second nucleotide sequence containing at least one ribonucleotide.

[0133] Nucleotide sequence Y is a base sequence of nucleotides constituting the second oligonucleotide, and includes a second nucleotide sequence. The second nucleotide sequence is a base sequence of nucleotides constituting the second nucleotide sequence portion.

[0134] The number of nucleotides contained in Y is 4 to 100, preferably 4 to 50. The number of nucleotides contained in Y may be the same as or different from the number of nucleotides contained in X. The number of nucleotides contained in Y is usually selected depending on other factors such as the strength of the antisense effect on the target RNA, the stability of the intramolecular hybridized structure, cost, and synthesis yield. The difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably 10 or less, more preferably 5 or less, even more preferably 4 or less, even more preferably 2 or less, and particularly preferably 0.

[0135] Xz is a group derived from a third oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and the deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides are each independently unmodified or modified at least at one of the base moiety and the phosphate moiety. The third oligonucleotide has the nucleotide sequence Xz.

[0136] The nucleotide sequence Xz is a base sequence of nucleotides constituting the third oligonucleotide. The nucleotide sequence Xz may or may not contain a third nucleotide sequence that enables hybridization with at least a portion of the fourth oligonucleotide. The third nucleotide sequence is a base sequence of nucleotides constituting the third nucleotide sequence portion.

[0137] The number of nucleotides contained in Xz is 7 to 100, preferably 10 to 50, more preferably 10 to 30, even more preferably 12 to 20 bases, and particularly preferably 13 to 14 bases. The number of nucleotides contained in Xz is usually selected depending on other factors such as the strength of the antisense effect on the target RNA, the stability of the intramolecular hybridized structure, cost, and synthesis yield.

[0138] Yz is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and the deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides are each independently unmodified or modified at least at one of the base moiety and the phosphate moiety. The fourth oligonucleotide has the nucleotide sequence Yz.

[0139] The nucleotide sequence Yz is a base sequence of nucleotides constituting the fourth oligonucleotide. The nucleotide sequence Yz may or may not contain a fourth nucleotide sequence that enables hybridization with at least a portion of the third oligonucleotide. The fourth nucleotide sequence is a base sequence of nucleotides constituting the fourth nucleotide sequence portion.

[0140] The preferred number of nucleotides contained in Yz is the same as that of Xz.

[0141] X and Y hybridize intramolecularly at the first nucleotide sequence portion and the second nucleotide sequence portion. When the single-stranded oligonucleotide of the present invention contains both Xz and Yz, Xz and Yz may or may not hybridize intramolecularly at the third nucleotide sequence portion and the fourth nucleotide sequence portion.

[0142] The first nucleotide sequence and the second nucleotide sequence do not need to be completely complementary in order for the first nucleotide sequence portion and the second nucleotide sequence portion to hybridize, but the complementarity is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, 99% or more). The first nucleotide sequence and the second nucleotide sequence may be completely complementary. The same is true for the third and fourth nucleotide sequences.

[0143] Nucleotide sequence X and nucleotide sequence Y do not need to be completely complementary in order for X and Y to hybridize, but the complementarity is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, 99% or more). Nucleotide sequence X and nucleotide sequence Y may be completely complementary. The same applies to nucleotide sequence Xz and nucleotide sequence Yz.

[0144] The first nucleotide sequence preferably contains 4 to 25 consecutive nucleotides. The first nucleotide sequence is preferably a sequence independently selected from deoxyribonucleotides and sugar-modified nucleotides, more preferably a sequence containing at least four nucleotides recognized by RNase H, and even more preferably a sequence containing consecutive deoxyribonucleotides. In another embodiment, the first nucleotide sequence contains at least one sugar-modified nucleotide and does not contain an oligonucleotide sequence consisting of four consecutive deoxyribonucleotides. These consecutive nucleotides may be identical to or different from each other. Furthermore, the first nucleotide sequence may or may not be an antisense sequence.

[0145] Furthermore, from the viewpoint of excellent pharmacokinetics, it is preferable that at least one nucleotide in the first nucleotide sequence portion is phosphorothioated. It is more preferable that at least one of the 3'- and 5'-nucleotides in the first nucleotide sequence portion is phosphorothioated. It is even more preferable that 80% of the nucleotides in the first nucleotide sequence portion are phosphorothioated, and even more preferable that 90% of the nucleotides are phosphorothioated. It is particularly preferable that the nucleotides contained in the first nucleotide sequence portion are linked to each other via phosphorothioate bonds. Further details will be described below.

[0146] The second nucleotide sequence preferably contains at least 4 consecutive nucleotides that are cleaved by RNase H, more preferably 4 to 25 consecutive nucleotides. These consecutive nucleotides may be the same or different. The second nucleotide sequence portion preferably contains an oligoribonucleotide, more preferably RNA. It is particularly preferred that the nucleotides contained in the second nucleotide sequence portion are linked to each other via phosphodiester bonds. Further details will be described below.

[0147] At least one of nucleotide sequence X, nucleotide sequence Xz, and nucleotide sequence Yz comprises an antisense sequence capable of hybridizing with at least a portion of a target RNA.

[0148] The types, numbers, and modification positions of sugar-modified nucleotides, deoxyribonucleotides, and ribonucleotides in X may affect the antisense effect, etc., of the single-stranded oligonucleotide. The preferred embodiments vary depending on the types, sequences, etc. of the nucleotides to be modified, and therefore cannot be generalized. However, as with the antisense sequence portion described above, they can be identified by measuring the antisense effect of the single-stranded oligonucleotide after modification. Y, Xz, and Yz are the same as X.

[0149] When two or more of X, Xz, and Yz hybridize to the same target RNA, their antisense sequences may be the same or different, or X, Xz, and Yz may hybridize to different target RNAs.

[0150] It is preferable that each of the antisense sequences independently contains "at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA" or "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides."

[0151] When the antisense sequence portion hybridizes intramolecularly as described below, the antisense sequence portion is recognized by a nuclease such as RNase H in a specific cell, and the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" is degraded to generate an oligonucleotide containing the antisense sequence portion, making it easier to exert an antisense effect.From this perspective, it is preferable that the antisense sequence portion contains "at least four consecutive nucleotides that are recognized by RNase H when hybridized with target RNA."

[0152] When nucleotide sequence X comprises an antisense sequence, Y may comprise a "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion." When the first nucleotide sequence is an antisense sequence, the antisense sequence portion (first nucleotide sequence portion) hybridizes with the second nucleotide sequence portion.

[0153] When the nucleotide sequence Xz contains an antisense sequence, Yz may contain a "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion." That is, the antisense sequence portion contained in Xz may be a third nucleotide sequence portion that can hybridize with at least a part of the fourth oligonucleotide (fourth nucleotide sequence portion).

[0154] When the nucleotide sequence Yz contains an antisense sequence, Xz may contain a "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion." That is, the antisense sequence portion contained in Yz may be a fourth nucleotide sequence portion that can hybridize with at least a part of the third oligonucleotide (third nucleotide sequence portion).

[0155] Next, each of the following aspects will be explained in order: [A] when nucleotide sequence X contains an antisense sequence; [B] when nucleotide sequence Xz contains an antisense sequence; and [C] when nucleotide sequence Yz contains an antisense sequence.

[0156] [A] When nucleotide sequence X contains an antisense sequence When the nucleotide sequence X comprises an antisense sequence, m is 0 or 1 and n is 0 or 1.

[0157] When nucleotide sequence X includes an antisense sequence, the first nucleotide sequence is preferably an antisense sequence. Although detailed explanations will be given below, embodiments of the present invention are not limited thereto. For example, the first nucleotide sequence may partially overlap with the antisense sequence, or may not overlap at all.

[0158] When the first nucleotide sequence is an antisense sequence, the first nucleotide sequence that is the antisense sequence is preferably a sequence that includes "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA," or a sequence that "includes at least one sugar-modified nucleotide and does not include an oligonucleotide chain consisting of four consecutive deoxyribonucleotides." From the viewpoint that the antisense sequence portion is recognized by a nuclease such as RNase H in a specific cell, and the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" is degraded to generate an oligonucleotide containing the antisense sequence portion and easily exert an antisense effect, the first nucleotide sequence that is the antisense sequence is preferably a sequence that includes "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA." In this case, preferred aspects of the first nucleotide sequence and first nucleotide sequence portion are the same as those of the antisense sequence and antisense sequence portion, which include "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA." Furthermore, it is preferred that 1 to 10 sugar-modified nucleotides are bound adjacent to at least one of the 3' and 5' ends of the first nucleotide sequence portion, and these one or more sugar-modified nucleotides are the same as those adjacent to at least one of the 3' and 5' ends of "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA" (antisense sequence portion). When the first nucleotide sequence is a sequence "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," preferred embodiments of the first nucleotide sequence and first nucleotide sequence portion are the same as those described for the antisense sequence and antisense sequence portion, which "contain at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides." Furthermore, 1 to 10 sugar-modified nucleotides may or may not be bound adjacent to at least one of the 3' and 5' ends of the first nucleotide sequence portion, and these one or more sugar-modified nucleotides are the same as the one or more sugar-modified nucleotides adjacent to at least one of the 3' and 5' ends of the "at least four consecutive nucleotides recognized by RNase H when hybridized to the target RNA" (antisense sequence portion).

[0159] In addition to the common features described above, the first nucleotide sequence preferably contains 4 to 20 consecutive nucleotides, more preferably 5 to 16 consecutive nucleotides, even more preferably 6 to 12 consecutive nucleotides, even more preferably 8 to 10 consecutive nucleotides, and particularly preferably 8 to 10 consecutive deoxyribonucleotides.

[0160] When n is 0, the second nucleotide sequence preferably contains, in addition to the common points, 4 to 25 consecutive nucleotides, more preferably 6 to 20 consecutive nucleotides, even more preferably 8 to 15 consecutive nucleotides, and particularly preferably 10 to 13 consecutive nucleotides.

[0161] When n is 0, degradation of the single-stranded oligonucleotide by RNase A or other RNases is suppressed until the single-stranded oligonucleotide is delivered into the nucleus of a specific cell, and in addition, when a group derived from the second oligonucleotide is degraded by a nuclease such as RNase H in the specific cell, an oligonucleotide comprising the antisense sequence portion, which is at least a part of the first oligonucleotide, is generated, and the antisense effect is easily exerted. Therefore, it is preferred that at least one of the 5'- and 3'-ends of the second nucleotide sequence portion be linked to the adjacent nucleotide via a phosphorothioate bond. When Y is linked to L at the 5'-end, it is more preferred that the 3'-end of the second nucleotide sequence portion be linked to the adjacent nucleotide via a phosphorothioate bond. When Y is linked to L at the 3'-end, it is more preferred that the 5'-end of the second nucleotide sequence portion be linked to the adjacent nucleotide via a phosphorothioate bond. Furthermore, from the viewpoint of suppressing degradation by enzymes such as RNases, it is preferred that 1 to 10 sugar-modified nucleotides be linked adjacent to at least one of the 5'- and 3'-ends of the second nucleotide sequence portion. When Y is bound to L at the 5' side, it is more preferable that 1 to 7 sugar-modified nucleotides are bound adjacent to the 3' side of the second nucleotide sequence portion, even more preferable that 2 to 5 sugar-modified nucleotides are bound, and even more preferable that 2 or 3 sugar-modified nucleotides are bound. When Y is bound to L at the 3' side, it is more preferable that 1 to 7 sugar-modified nucleotides are bound adjacent to the 5' side of the second nucleotide sequence portion, even more preferable that 2 to 5 sugar-modified nucleotides are bound, and even more preferable that 2 or 3 sugar-modified nucleotides are bound. Here, a plurality of deoxyribonucleotides or ribonucleotides, or both, may be contained between the plurality of sugar-modified nucleotides on at least one of the 3' side and the 5' side, but it is preferable that the plurality of sugar-modified nucleotides are contiguous.When multiple sugar-modified nucleotides are bound adjacently to at least one of the 3'- and 5'-ends of the second nucleotide sequence portion, the phrase "multiple sugar-modified nucleotides are bound adjacently" means that the multiple sugar-modified nucleotides and an oligonucleotide chain consisting of deoxyribonucleotides and ribonucleotides contained between the multiple sugar-modified nucleotides are bound adjacently. When multiple sugar-modified nucleotides are bound adjacently to at least one of the 3'- and 5'-ends of the second nucleotide sequence portion, the sugar-modified nucleotides may be the same or different.

[0162] When n is 0, the sugar-modified nucleotide portion bound adjacent to at least one of the 3' and 5' sides of the second nucleotide sequence portion may or may not hybridize to a portion of the first oligonucleotide, but it is preferable that it hybridizes to a portion of the first oligonucleotide.

[0163] When n is 0, the sugar-modified nucleotide attached adjacent to at least one of the 5'-side and 3'-side of the second nucleotide sequence portion is preferably a 2'-O-methylated nucleotide, a 2'-O-methoxyethyl (2'-MOE)-modified nucleotide, a 2'-O-aminopropyl (2'-AP)-modified nucleotide, a 2'-fluorolated nucleotide, a 2'-F-arabinonucleotide (2'-F-ANA), a bridged nucleotide (BNA (Bridged Nucleic Acid)), or a 2'-O-methylcarbamoylethyl (2'-MCE)-modified nucleotide, more preferably a BNA, a 2'-O-methylated nucleotide, a 2'-MOE-modified nucleotide, or a 2'-MCE-modified nucleotide, even more preferably a BNA or a 2'-O-methylated nucleotide, still more preferably an LNA containing a partial structure represented by the following formula (II) or a 2'-O-methylated nucleotide, and particularly preferably a 2'-O-methylated nucleotide.

[0164] [ka]

[0165] In the formula, Base represents a base moiety and is a purin-9-yl group or a 2-oxo-pyrimidin-1-yl group, and the purin-9-yl group and the 2-oxo-pyrimidin-1-yl group are unmodified or modified.

[0166] When n is 0, the number of nucleotides in the oligonucleotide adjacent to at least one of the 5'-side and 3'-side of the second nucleotide sequence portion may be the same as or different from the number of nucleotides in the oligonucleotide adjacent to at least one of the 5'-side and 3'-side of the first nucleotide sequence portion (e.g., the antisense sequence portion to which the second nucleotide sequence portion hybridizes), but the difference is preferably within 3, more preferably within 1, and particularly preferably the same. When an oligonucleotide chain comprising one or more sugar-modified nucleotides is bound adjacent to the 3'-side of the second nucleotide sequence portion, the number of nucleotides in that oligonucleotide chain may be the same as or different from the number of nucleotides in the oligonucleotide chain comprising one or more sugar-modified nucleotides bound adjacent to the 5'-side of the first nucleotide sequence portion, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same. When an oligonucleotide chain containing one or more sugar-modified nucleotides is bound adjacent to the 5' side of the second nucleotide sequence portion, the number of nucleotides in that oligonucleotide chain may be the same as or different from the number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides bound adjacent to the 3' side of the first nucleotide sequence portion, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same.

[0167] When n is 0 and a group derived from a functional molecule described below is linked to the second oligonucleotide directly or indirectly via a linking group, in addition to the above common features and the preferred examples when n is 0, it is preferable that the 5' and 3' ends of the second nucleotide sequence portion are linked to adjacent groups via phosphodiester bonds. In this case, the second nucleotide sequence preferably contains 4 to 30 consecutive nucleotides, more preferably 8 to 25 consecutive nucleotides, even more preferably 10 to 20 consecutive nucleotides, and particularly preferably 12 to 16 consecutive nucleotides.

[0168] When n is 1, the second nucleotide sequence is the same as the second nucleotide sequence described above in the common points, as well as the second nucleotide sequence described below in [C] When nucleotide sequence Yz contains an antisense sequence. When the first nucleotide sequence is an antisense sequence and nucleotide sequence Yz contains an antisense sequence, the second nucleotide sequence preferably contains 4 to 30 consecutive nucleotides, more preferably 8 to 25 consecutive nucleotides, even more preferably 10 to 20 consecutive nucleotides, and particularly preferably 12 to 16 consecutive nucleotides.

[0169] When n is 1, the form of the nucleotide bound adjacent to the second nucleotide sequence portion and the bond with the nucleotide are the same as in the case where the [C] nucleotide sequence Yz contains an antisense sequence, which will be described later.

[0170] When n is 1 and m is 1, Xz and Yz preferably hybridize at the third nucleotide sequence portion contained in Xz and the fourth nucleotide sequence portion contained in Yz.

[0171] When nucleotide sequence Xz further comprises an antisense sequence, preferred embodiments of Xz are the same as those described below in [B] When nucleotide sequence Xz comprises an antisense sequence. In this case, m is 1 and n is 0 or 1. When n is 1, the antisense sequence portion (third nucleotide sequence portion) contained in Xz may hybridize with the fourth nucleotide sequence portion contained in Yz, and preferred embodiments of Yz are the same as those described below in [B] When nucleotide sequence Xz comprises an antisense sequence.

[0172] When nucleotide sequence Yz further comprises an antisense sequence, preferred embodiments of Yz are the same as those described below when [C] nucleotide sequence Yz comprises an antisense sequence. In this case, m is 0 or 1, and n is 1. When m is 1, the antisense sequence portion (fourth nucleotide sequence portion) comprised in Yz may hybridize with the third nucleotide sequence portion comprised in Xz, and preferred embodiments of Xz are the same as those described below when [C] nucleotide sequence Yz comprises an antisense sequence.

[0173] [B] When the nucleotide sequence Xz contains an antisense sequence When the nucleotide sequence Xz contains an antisense sequence, m is 1 and n is 0 or 1.

[0174] When the nucleotide sequence Xz comprises an antisense sequence, n is 1, and the third nucleotide sequence hybridizes with the fourth nucleotide sequence, it is preferable that the third nucleotide sequence is an antisense sequence. Although detailed explanations will be given below, embodiments of the present invention are not limited thereto. For example, the third nucleotide sequence may partially overlap with the antisense sequence, or may not overlap at all.

[0175] The antisense sequence portion contained in Xz may be a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA," or a sequence containing "at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," but the antisense sequence is preferably a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA." The preferred forms of the sequence are the same as those described above for the antisense sequence and antisense sequence portion, and the same applies to one or more sugar-modified nucleotides bound adjacent to the 3' side of the antisense sequence portion and one or more sugar-modified nucleotides bound adjacent to the 5' side of the antisense sequence portion.

[0176] At least one sugar-modified nucleotide may or may not be bound adjacent to at least one of the 5'-side and 3'-side of the first nucleotide sequence portion. When at least one sugar-modified nucleotide is bound adjacent to at least one of the 5'-side and 3'-side of the first nucleotide sequence portion, it is more preferable that when X is bound to L at the 5'-side, at least one sugar-modified nucleotide is bound adjacent to the 3'-side of the first nucleotide sequence portion, and it is more preferable that when X is bound to L at the 3'-side, at least one sugar-modified nucleotide is bound adjacent to the 5'-side of the first nucleotide sequence portion.

[0177] The first nucleotide sequence may be the same as the first nucleotide sequence described in the common points above, and is preferably 4 to 20 consecutive nucleotides, more preferably 6 to 20 consecutive nucleotides, more preferably 8 to 16 consecutive nucleotides, and particularly preferably 9 to 15 consecutive deoxyribonucleotides. Furthermore, when the first nucleotide sequence is an antisense sequence, preferred embodiments of the first nucleotide sequence are the same as those when [A] nucleotide sequence X includes an antisense sequence.

[0178] When n is 0, Y (including the second nucleotide sequence, etc.) is the same as when n is 0 in the case where the nucleotide sequence X contains an antisense sequence ([A] above). When n is 1, Y (including the second nucleotide sequence, etc.) is the same as when n is 1 in the case where the nucleotide sequence X contains an antisense sequence ([A] above).

[0179] When n is 1, it is preferable that the antisense sequence portion (third nucleotide sequence portion) contained in Xz hybridizes with the fourth nucleotide sequence portion contained in Yz, and preferred embodiments of the fourth nucleotide sequence portion for this purpose are the same as those of the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion." In particular, the fourth nucleotide sequence preferably contains 9 to 20 nucleotides, and more preferably contains 9 to 14 nucleotides.

[0180] A preferred embodiment of the fourth nucleotide sequence portion is the same as the "nucleotide sequence portion that intramolecularly hybridizes with the antisense sequence portion" and is the same as the second nucleotide sequence portion when n is 0 in the case where the nucleotide sequence X contains an antisense sequence ([A]).

[0181] The form of the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the fourth nucleotide sequence portion is the same as the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the second nucleotide sequence portion when n is 0 in the case where the nucleotide sequence X contains an antisense sequence (A).

[0182] The sugar-modified nucleotide moiety attached adjacent to at least one of the 3'-side and 5'-side of the fourth nucleotide sequence portion may or may not hybridize to a portion of the third oligonucleotide, but preferably hybridizes to a portion of the third oligonucleotide. The number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides attached adjacent to at least one of the 5'-side and 3'-side of the fourth nucleotide sequence portion may be the same as or different from the number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides attached adjacent to at least one of the 5'-side and 3'-side of the antisense sequence portion contained in Xz, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same. When the oligonucleotide chain containing one or more sugar-modified nucleotides is attached adjacent to the 3'-side of the fourth nucleotide sequence portion, the number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides attached adjacent to the 5'-side of the antisense sequence portion contained in Xz may be the same as or different from the number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides attached adjacent to the 5'-side of the antisense sequence portion contained in Xz, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same. When an oligonucleotide chain containing one or more sugar-modified nucleotides is bound adjacent to the 5' side of the fourth nucleotide sequence portion, the number of nucleotides may be the same as or different from the number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides bound adjacent to the 3' side of the antisense sequence portion contained in Xz, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same.

[0183] [C] When the nucleotide sequence Yz contains an antisense sequence When the nucleotide sequence Yz contains an antisense sequence, m is 0 or 1, and n is 1.

[0184] When the nucleotide sequence Yz includes an antisense sequence, m is 1, and the fourth nucleotide sequence hybridizes with the third nucleotide sequence, it is preferable that the fourth nucleotide sequence is an antisense sequence. Although detailed explanations will be given below, embodiments of the present invention are not limited thereto. For example, the fourth nucleotide sequence may partially overlap with the antisense sequence, or may not overlap at all.

[0185] The antisense sequence contained in Yz is preferably a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA," or a sequence containing "at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," and the antisense sequence is more preferably a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA." The preferred forms of the sequence are the same as those described above for the antisense sequence and antisense sequence portion, and the same applies to one or more sugar-modified nucleotides attached adjacent to the 3' side of the antisense sequence portion and one or more sugar-modified nucleotides attached adjacent to the 5' side of the antisense sequence portion.

[0186] From the viewpoint that degradation by RNA-degrading enzymes such as RNase A is suppressed until the single-stranded oligonucleotide is delivered into the nucleus of a specific cell, and that the second nucleotide sequence portion is degraded by RNase H within the specific cell to generate an oligonucleotide that is a part of the fourth oligonucleotide and includes the antisense sequence portion, and that the antisense effect is easily exerted, it is preferable that the 5' and 3' ends of the second nucleotide sequence portion be linked to adjacent groups by phosphodiester bonds.

[0187] Furthermore, at least one sugar-modified nucleotide may or may not be bound adjacent to at least one of the 5' and 3' ends of the second nucleotide sequence portion. When at least one sugar-modified nucleotide is bound adjacent to the second nucleotide sequence portion, it is more preferable that when Y is bound to L at the 5' end, at least one sugar-modified nucleotide is bound adjacent to the 3' end of the second nucleotide sequence portion, and it is more preferable that when Y is bound to L at the 3' end, at least one sugar-modified nucleotide is bound adjacent to the 5' end of the second nucleotide sequence portion.

[0188] In addition to the aspects of the second nucleotide sequence described above in the common points, the second nucleotide sequence preferably contains 4 to 25 consecutive nucleotides, more preferably 10 to 22 consecutive nucleotides, even more preferably 10 to 16 consecutive nucleotides, and particularly preferably 12 to 13 consecutive ribonucleotides.

[0189] The first nucleotide sequence may be the same as the first nucleotide sequence described in the common points above, and is preferably 4 to 20 consecutive nucleotides, more preferably 6 to 20 consecutive nucleotides, more preferably 8 to 16 consecutive nucleotides, and particularly preferably 9 to 15 consecutive deoxyribonucleotides. Furthermore, when the first nucleotide sequence is an antisense sequence, preferred embodiments of the first nucleotide sequence are the same as those when [A] nucleotide sequence X includes an antisense sequence.

[0190] As described above, degradation of the single-stranded oligonucleotide by RNase A or other RNA-degrading enzymes is inhibited until the single-stranded oligonucleotide is delivered into the nucleus of a specific cell, and in the specific cell, a group derived from the second oligonucleotide is degraded by nucleases such as RNase H to generate an oligonucleotide comprising the antisense sequence portion, which is at least a part of the fourth oligonucleotide, and from the viewpoint of easily exerting an antisense effect, it is preferred that at least one of the 5' and 3' ends of the first nucleotide sequence portion be linked to the adjacent nucleotide via a phosphorothioate bond. When X is linked to L at the 5' end, it is more preferred that the 3' end of the first nucleotide sequence portion be linked to the adjacent nucleotide via a phosphorothioate bond, and when X is linked to L at the 3' end, it is more preferred that the 5' end of the first nucleotide sequence portion be linked to the adjacent nucleotide via a phosphorothioate bond.

[0191] Furthermore, when m is 0, from the viewpoint of suppressing degradation by enzymes such as RNase, it is preferable that 1 to 10 sugar-modified nucleotides are linked adjacent to at least one of the 5'-side and 3'-side of the first nucleotide sequence portion. When X is linked to L at the 5'-side, it is more preferable that 1 to 7 sugar-modified nucleotides are linked adjacent to the 3'-side of the first nucleotide sequence portion, even more preferable that 2 to 5 sugar-modified nucleotides are linked, and even more preferable that 2 or 3 sugar-modified nucleotides are linked. When X is linked to L at the 3'-side, it is more preferable that 1 to 7 sugar-modified nucleotides are linked adjacent to the 5'-side of the first nucleotide sequence portion, even more preferable that 2 to 5 sugar-modified nucleotides are linked, and even more preferable that 2 or 3 sugar-modified nucleotides are linked. Here, a plurality of deoxyribonucleotides or ribonucleotides, or both, may be contained between the plurality of sugar-modified nucleotides on at least one of the 3'-side and 5'-side, but it is preferable that the plurality of sugar-modified nucleotides are contiguous. When a plurality of sugar-modified nucleotides are bound adjacently to at least one of the 3'-side and 5'-side of the first nucleotide sequence portion, the phrase "a plurality of sugar-modified nucleotides are bound adjacently" means that the plurality of sugar-modified nucleotides and an oligonucleotide chain consisting of deoxyribonucleotides and ribonucleotides contained between the plurality of sugar-modified nucleotides are bound adjacently. When a plurality of sugar-modified nucleotides are bound adjacently to at least one of the 3'-side and 5'-side of the first nucleotide sequence portion, the respective sugar-modified nucleotides may be the same or different.

[0192] When m is 0, the sugar-modified nucleotide portion bound adjacent to at least one of the 3' and 5' sides of the first nucleotide sequence portion may or may not hybridize to a portion of the second oligonucleotide, but it is preferable that it hybridizes to a portion of the second oligonucleotide.

[0193] When m is 0, the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the first nucleotide sequence portion is the same as the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the second nucleotide sequence when n is 0 in the case where the nucleotide sequence X in [A] comprises an antisense sequence.

[0194] When m is 1, it is preferable that the antisense sequence portion (fourth nucleotide sequence portion) contained in Yz hybridizes with the third nucleotide sequence portion contained in Xz, and preferred embodiments of the third nucleotide sequence portion for this purpose are the same as those of the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion." In particular, the third nucleotide sequence preferably contains 9 to 20 nucleotides, and more preferably contains 9 to 14 nucleotides.

[0195] The third nucleotide sequence portion contained in Xz is preferably linked to the adjacent nucleotide via a phosphorothioate bond at least on one side of the 5' and 3' ends, from the viewpoint that degradation by RNases such as RNase A is inhibited until the single-stranded oligonucleotide is delivered into the nucleus of a specific cell, and that degradation of the group derived from the third oligonucleotide by a nuclease such as RNase H in the specific cell produces an oligonucleotide that is at least a part of the fourth oligonucleotide and includes the antisense sequence portion contained in Yz, thereby easily exerting an antisense effect. When X is linked to L at the 5' end, it is more preferable that the 3' end of the third nucleotide sequence portion is linked to the adjacent nucleotide via a phosphorothioate bond, and when X is linked to L at the 3' end, it is more preferable that the 5' end of the third nucleotide sequence portion is linked to the adjacent nucleotide via a phosphorothioate bond. Furthermore, from the viewpoint of inhibiting degradation by enzymes such as RNases, it is preferable that 1 to 10 sugar-modified nucleotides are linked adjacent to at least one of the 5' and 3' ends of the third nucleotide sequence portion. When X is bound to L at the 5' side, it is more preferable that 1 to 7 sugar-modified nucleotides are bound adjacent to the 3' side of the third nucleotide sequence portion, even more preferably that 2 to 5 sugar-modified nucleotides are bound, and even more preferably that 2 or 3 sugar-modified nucleotides are bound. When X is bound to L at the 3' side, it is more preferable that 1 to 7 sugar-modified nucleotides are bound adjacent to the 5' side of the third nucleotide sequence portion, even more preferably that 2 to 5 sugar-modified nucleotides are bound, and even more preferably that 2 or 3 sugar-modified nucleotides are bound. Furthermore, when the nucleotide sequence X further comprises an antisense sequence, the above-mentioned aspects of Xz are preferred from the viewpoint that an oligonucleotide comprising the antisense sequence portion as at least a part of the first oligonucleotide is produced and is therefore more likely to exert an antisense effect.Here, a plurality of deoxyribonucleotides, ribonucleotides, or both may be present between the plurality of sugar-modified nucleotides on at least one of the 3'- and 5'-sides, but it is preferable that the plurality of sugar-modified nucleotides are contiguous. When a plurality of sugar-modified nucleotides are bound adjacently to at least one of the 3'- and 5'-sides of the third nucleotide sequence portion, the phrase "a plurality of sugar-modified nucleotides are bound adjacently" means that the plurality of sugar-modified nucleotides and the oligonucleotide chains composed of deoxyribonucleotides and ribonucleotides contained between the plurality of sugar-modified nucleotides are bound adjacently. When a plurality of sugar-modified nucleotides are bound adjacently to at least one of the 3'- and 5'-sides of the third nucleotide sequence portion, the respective sugar-modified nucleotides may be the same or different.

[0196] The sugar-modified nucleotide portion bound adjacent to at least one of the 3' and 5' sides of the third nucleotide sequence portion may or may not hybridize to a portion of the fourth oligonucleotide, but it is preferable that it hybridizes to a portion of the fourth oligonucleotide. The number of nucleotides in the oligonucleotide adjacent to at least one of the 5'-side and 3'-side of the third nucleotide sequence portion may be the same as or different from the number of nucleotides in the oligonucleotide adjacent to at least one of the 5'-side and 3'-side of the antisense sequence portion contained in Yz, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same. When the oligonucleotide chain containing one or more sugar-modified nucleotides is bound adjacent to the 3'-side of the third nucleotide sequence portion, the number of nucleotides in the oligonucleotide chain may be the same as or different from the number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides bound adjacent to the 5'-side of the antisense sequence portion contained in Yz, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same. When an oligonucleotide chain containing one or more sugar-modified nucleotides is bound adjacent to the 5' side of the third nucleotide sequence portion, the number of nucleotides in that oligonucleotide chain may be the same as or different from the number of nucleotides in an oligonucleotide chain containing one or more sugar-modified nucleotides that is bound adjacent to the 3' side of the antisense sequence portion contained in Yz, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same.

[0197] The form of the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the third nucleotide sequence portion is the same as that of the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the second nucleotide sequence portion when n is 0 and [A] nucleotide sequence X is an antisense sequence.

[0198] Next, L, Lx, Ly and the functional molecule will be described. The following is common to several of the above-mentioned embodiments.

[0199] L is a linking group containing a non-nucleotide structure or a group of the formula: -P 5 -W 5 -P 5 - (In the formula, P 5 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 5 is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and is a linker connecting the aforementioned X and Y. L connects the aforementioned X and Y in the order of XLY.

[0200] Lx is -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or a group represented by the following formula: -P 6 -W 6 -P 6 - (In the formula, P 6 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 6 is a group derived from an oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and is a linker linking the aforementioned X and Xz. Lx links the aforementioned X and Xz in the order of Xz-Lx-X. When Lx is -P(=O)(OH)-, Xz and X are directly linked via a phosphodiester bond of the nucleotide.

[0201] Ly is a linking group comprising a non-nucleotide structure or a linking group of the formula: -P 7 -W 7 -P 7 - (In the formula, P 7 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 7is a group derived from an oligonucleotide Ly consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and is a linker linking the aforementioned Y and Yz. Ly links the aforementioned Y and Yz in the order Y-Ly-Yz. When Ly is -P(=O)(OH)-, Y and Yz are directly linked via a phosphodiester bond of the nucleotide.

[0202] At least one of L, Lx, and Ly is a linking group containing a non-nucleotide structure. When the single-stranded oligonucleotide of the present invention has two or more linking groups containing a non-nucleotide structure, the respective linking groups containing a non-nucleotide structure may be the same or different.

[0203] When m is 0 and n is 0, L is a linking group containing the non-nucleotide structure. When m is 1 and n is 0, at least one of L and Lx is a linking group containing the non-nucleotide structure. When m is 0 and n is 1, at least one of L and Ly is a linking group containing the non-nucleotide structure. When m is 1 and n is 1, at least one of L, Lx, and Ly is a linking group containing the non-nucleotide structure.

[0204] A "linking group containing a non-nucleotide structure" is a linking group that has at least one "non-nucleotide structure" as a constituent unit. An example of a non-nucleotide structure is a structure that does not have a base. A "linking group containing a non-nucleotide structure" may or may not contain a nucleotide (deoxyribonucleoside group, ribonucleoside group, etc.). Examples of "linking groups containing a non-nucleotide structure" include the following groups:

[0205] In some embodiments, the linking group containing a non-nucleotide structure is a group of the following formula: [ka] {where, V 11 teeth, C 2-50 Alkylene group (C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more independently selected substituents from The following formulas (XIII-1) to (XIII-11):

[0206] [ka] (In the formula, о 1 is an integer between 0 and 30, and p 1 is an integer between 0 and 30, and d 1 is an integer of 1 to 10, w is an integer of 0 to 3, Rb is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkoxy group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxy group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group or C 1-6 is an alkyl group, and Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6Alkylaminosulfonyl group or diC 1-6 alkylaminosulfonyl group) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 11 is C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more substituents independently selected from the following), or a group selected from the formulas (XIII-1) to (XIII-11): Substituent group V a means a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, P 11 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 11 is -P(=O)(OH)-, q 11 is an integer between 1 and 10, and q 12 is an integer between 1 and 20, and q 11 and q 12 When at least one of these is 2 or more, V 11 are the same or different}.

[0207] Here, o 1 is preferably an integer from 1 to 30, and p 1 is preferably an integer from 1 to 30. 11 is preferably an integer from 1 to 6, more preferably an integer from 1 to 3. 12 is preferably an integer of 1 to 6, more preferably an integer of 1 to 3. 11 is preferably —P(═O)(OH)—.

[0208] In some embodiments, the linking group containing a non-nucleotide structure is a group of the following formula: [ka] {where, V 1 teeth, C 2-50 Alkylene group (C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more independently selected substituents from The following equations (XI-1) to (XI-10):

[0209] [ka] (In the formula, о 1 is an integer between 0 and 30, and p 1 is an integer between 0 and 30, and d 1 is an integer of 1 to 10, w is an integer of 0 to 3, Rb is a halogen atom, a hydroxy group, an amino group, C 1-6 Alkoxy group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxy group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group or C 1-6 alkyl group) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 1 is C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more substituents independently selected from the following), or a group selected from formulas (XI-1) to (XI-10): Substituent group V ameans a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, P 1 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 1 is -P(=O)(OH)-, q3 is an integer of 1 to 10, q4 is an integer of 1 to 20, and when at least one of q3 and q4 is 2 or more, V 1 are the same or different}.

[0210] Here, o 1 is preferably an integer from 1 to 30, and p 1 is preferably an integer of 1 to 30. q3 is preferably an integer of 1 to 6, more preferably an integer of 1 to 3. q4 is preferably an integer of 1 to 6, more preferably an integer of 1 to 3. P 1 is preferably —P(═O)(OH)—.

[0211] In some embodiments, the linking group containing a non-nucleotide structure is a group of the following formula: [ka] {where, V 0 teeth, C 2-50 Alkylene group (C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more independently selected substituents from The following formulas (X-1) to (X-9):

[0212] [ka] (wherein o is an integer from 0 to 30, and p is an integer from 0 to 30). a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 0 is C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a substituted with one or more substituents independently selected from the following), or a group selected from the formulae (X-1) to (X-9), Substituent group V a means a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, q1 is an integer of 1 to 10, q2 is an integer of 1 to 20, and when at least one of q1 and q2 is 2 or more, V 0 are the same or different}.

[0213] Here, o is preferably an integer of 1 to 30, and p is preferably an integer of 1 to 30. q1 is preferably an integer of 1 to 6, more preferably an integer of 1 to 3. q2 is preferably an integer of 1 to 6, more preferably an integer of 1 to 3.

[0214] L and X are linked by a covalent bond, and for example, it is preferred that the oxygen atom obtained by removing a hydrogen atom from the hydroxy group of the sugar moiety of the terminal nucleotide of X (including a partial structure replaced by the sugar backbone in the case of a sugar-modified nucleotide) is linked to L. L and Y are linked by a covalent bond, and for example, it is preferred that the oxygen atom obtained by removing a hydrogen atom from the hydroxy group of the sugar moiety of the terminal nucleotide of Y (including a partial structure replaced by the sugar backbone in the case of a sugar-modified nucleotide) is linked to L. Similarly, Lx and X are preferably linked via the sugar moiety of the terminal nucleotide of X, and Lx and Xz are preferably linked via the sugar moiety of the terminal nucleotide of Xz. Similarly, Ly and Y are preferably linked via the sugar moiety of the terminal nucleotide of Y, and Ly and Yz are preferably linked via the sugar moiety of the terminal nucleotide of Yz. When the terminal nucleotide is a sugar-modified nucleotide, the sugar moiety contains a partial structure that replaces the sugar backbone.

[0215] When X binds to L on the 3' side, Y binds to L on the 5' side. Furthermore, when m is 1, X binds to Lx on the 5' side, and Xz binds to Lx on the 3' side. Furthermore, when n is 1, Y binds to Ly on the 3' side, and Yz binds to Ly on the 5' side.

[0216] When X binds to L on the 5' side, Y binds to L on the 3' side. Furthermore, when m is 1, X binds to Lx on the 3' side, and Xz binds to Lx on the 5' side. Furthermore, when n is 1, Y binds to Ly on the 5' side, and Yz binds to Ly on the 3' side.

[0217] It is desirable that L is degraded more quickly than the antisense sequence portion described above. The same applies to Lx and Ly.

[0218] The linking group containing a non-nucleotide structure in L is preferably represented by the following formula: [ka] {where, V 3 teeth, C 2-20 Alkylene group (the C 2-20 The alkylene group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, an amino group, and an oxo group; The following formulas (XIV-1) to (XIV-11): [ka] (In the formula, о 1 is an integer between 0 and 10, and p 1 is an integer between 0 and 10, and d 1 is an integer from 1 to 10, w is an integer from 0 to 2, Rc is a hydrogen atom, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkylcarbonyl group, C 1-6 Haloalkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, C 1-6 Haloalkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 alkylaminosulfonyl group) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 3 is C 2-20 Alkylene group (the C 2-20 The alkylene group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a hydroxy group, an amino group, and an oxo group), or a group selected from the formulas (XIV-1) to (XIV-11), P 3 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 3 is -P(=O)(OH)-, q5 is an integer of 1 to 10, q6 is an integer of 1 to 20, and when at least one of q5 and q6 is 2 or more, V 3 are the same or different}.

[0219] The linking group containing a non-nucleotide structure in L is more preferably represented by the following formula: [ka] (wherein r is an integer from 2 to 20). or a group represented by the following formula: [ka] (wherein s is an integer from 1 to 10) It is a group represented by the formula: The linking group containing a non-nucleotide structure in L is more preferably represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) It is a group represented by the formula:

[0220] In another embodiment, the linking group containing a non-nucleotide structure in L is preferably represented by the following formula: [ka] (In the formula, P 2 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and at least one P 2 is -P(=O)(OH)- and s 1is an integer between 1 and 10, and s 2 is an integer between 1 and 6) and more preferably a group represented by the following formula: [ka] (In the formula, P 2 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 1 is an integer between 1 and 10, and s 22 is an integer between 0 and 5) and more preferably a group represented by the following formula: [ka] (In the formula, s 1 is an integer between 1 and 10, and s 2 is an integer between 1 and 6) It is a group represented by the formula:

[0221] The above s 1 is preferably an integer of 1 to 6, more preferably an integer of 3 to 6. 2 is preferably an integer of 1 to 5, and more preferably an integer of 1 to 3. 22 is preferably an integer of 0 to 4, and more preferably an integer of 0 to 2.

[0222] In another embodiment, the linking group containing a non-nucleotide structure in L is preferably represented by the following formula: [ka] {where, V 2 is represented by the following formula (XII-1), (XII-3), (XII-7) or (XII-8):

[0223] [ka] (In the formula, о 2 is an integer from 1 to 6, and p 2 is an integer from 1 to 6, and d 2 is an integer of 1 to 6). Among these, a group represented by the following formula: [ka] {where, V 2 is represented by the following formula (XII-1), (XII-3), (XII-7) or (XII-8):

[0224] [ka] (In the formula, о 2 is an integer between 3 and 5, and p 2 is an integer between 3 and 5, and d 2 is a group represented by 4)}.

[0225] In another embodiment, the linking group containing a non-nucleotide structure in L is preferably represented by the following formula: [ka] {where, V 14 are each independently represented by the following formula (XIV-10) or (XIV-11): [ka] (Wherein, w is 0 or 1, Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 an alkylaminosulfonyl group, a ribonucleoside group, or a deoxyribonucleoside group), At least one V 14 is a group represented by the formula (XIV-10) or (XIV-11), P 14 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 14 is -P(=O)(OH)-, s 14 is an integer between 0 and 9, and s 14 When is 1 or more, V 14 are groups represented by the following formula: P 14 is preferably —P(═O)(OH)—. s 14 is preferably an integer of 2 to 6, and more preferably 3 or 4.

[0226] The linking group containing a non-nucleotide structure in L is more preferably represented by the following formula: [ka] (In the formula, P 4 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and at least one P 4 is -P(=O)(OH)- and s 4 is an integer between 1 and 10, and V 4are each independently represented by the following formula (XIV-10): [ka] (wherein w is 0 or 1), a ribonucleoside group or a deoxyribonucleoside group, and at least one V 4 is a group represented by the formula (XIV-10) More preferably, the formula: [ka] (In the formula, P 4 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 44 is an integer between 0 and 9, and V 4 are each independently represented by the following formula (XIV-10): [ka] (wherein w is 0 or 1), a ribonucleoside group or a deoxyribonucleoside group, and at least one V 4 is a group represented by the formula (XIV-10) Even more preferably, the formula: [ka] (In the formula, s 4 is an integer between 1 and 10, and V 4 are each independently represented by the following formula (XIV-10): [ka] (wherein w is 0 or 1), a ribonucleoside group or a deoxyribonucleoside group, and at least one V 4 is a group represented by the formula (XIV-10). 4is preferably an integer of 3 to 7, more preferably 4 or 5. 44 is preferably an integer of 2 to 6, and more preferably 3 or 4.

[0227] V 4 is preferably represented by the following formula (XV-10): [ka] (wherein w is 0 or 1), a ribonucleoside group or a deoxyribonucleoside group, 4 is a group represented by the formula (XV-10), and more preferably, the group represented by the following formula (XVI-10): [ka] (wherein w is 0 or 1), a ribonucleoside group or a deoxyribonucleoside group, 4 is a group represented by the formula (XVI-10), more preferably a group represented by the formula (XVI-10), particularly preferably a group represented by the following formula (XII-10): [ka] It is a group represented by the formula:

[0228] Regarding the formulae (XII-10), (XV-10), and (XVI-10), when two or more 2-methyltetrahydrofurans are linked via a phosphodiester bond or a phosphorothioate bond, the phosphodiester bond preferably links the 3-position of one tetrahydrofuran ring to the 2-position of the other tetrahydrofuran ring.

[0229] In another embodiment, the linking group containing a non-nucleotide structure in L is preferably represented by the following formula: [ka] {where, V 8 teeth, Formula (XV-11): [ka] (Wherein Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 an alkylaminosulfonyl group, a ribonucleoside group, or a deoxyribonucleoside group), At least one V 8 is a group represented by the formula (XV-11), P 8 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 8 is -P(=O)(OH)-, s 8 is an integer between 1 and 10, and s 8 When is 2 or more, V 8 are groups represented by the following formula: More preferably, the compound of the formula: [ka] {where, V 9 teeth, The following formula (XVI-11): [ka] (Wherein Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 an alkylaminosulfonyl group, a ribonucleoside group, or a deoxyribonucleoside group), At least one V 9 is a group represented by the formula (XVI-11), P 9 are each independently -P(=O)(OH)- or -P(=O)(SH)-; s 99 is an integer between 0 and 9, and s 99 When is 1 or more, V 9 are groups represented by the following formula: More preferably, the formula: [ka] {where, V 10 teeth, The following formula (XVII-11): [ka] (Wherein Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group or C 1-6 an alkoxycarbonyl group, or a ribonucleoside group), At least one V 10 is a group represented by the formula (XVII-11), s 10 is an integer between 1 and 10, and s 10 When is 2 or more, V 10 are the same or different groups. 10 is preferably an integer of 3 to 7, and more preferably 4 or 5.

[0230] The preferred linking group containing a non-nucleotide structure for Lx and the preferred linking group containing a non-nucleotide structure for Ly are the same as the preferred linking group containing a non-nucleotide structure for L.

[0231] L is a group of the formula:-P 5 -W 5 -P 5 - (In the formula, P 5 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 5 is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), the fifth oligonucleotide is preferably an oligonucleotide that is degraded under physiological conditions. 5 is preferably —P(═O)(OH)—.

[0232] Lx is represented by the following formula: -P6 -W 6 -P 6 - (In the formula, P 6 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 6 is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), the sixth oligonucleotide is preferably an oligonucleotide that is degraded under physiological conditions. 6 is preferably —P(═O)(OH)—.

[0233] Ly is a compound of the formula: -P 7 -W 7 -P 7 - (In the formula, P 7 are each independently -P(=O)(OH)- or -P(=O)(SH)-, W 7 is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), the seventh oligonucleotide is preferably an oligonucleotide that is degraded under physiological conditions. 7 is preferably —P(═O)(OH)—.

[0234] Here, the "oligonucleotide degradable under physiological conditions" may be an oligonucleotide that is degraded under physiological conditions by various enzymes such as DNase (deoxyribonuclease) and RNase (ribonuclease), and the nucleotides constituting the oligonucleotide may or may not be chemically modified at the base, sugar, or phosphate bond in part or all thereof. The "oligonucleotide degradable under physiological conditions" contains, for example, at least one phosphodiester bond.

[0235] The fifth oligonucleotide has hydroxy groups at the 3' and 5' ends, and the groups derived from the fifth oligonucleotide are groups obtained by removing hydrogen atoms from the hydroxy groups at the 3' and 5' ends, respectively. The sixth and seventh oligonucleotides are similar to the fifth oligonucleotide.

[0236] The fifth oligonucleotide is preferably an oligonucleotide linked by a phosphodiester bond, more preferably an oligodeoxyribonucleotide or oligoribonucleotide, even more preferably DNA or RNA, and even more preferably RNA. The sixth and seventh oligonucleotides are similar to the fifth oligonucleotide.

[0237] The fifth oligonucleotide may or may not contain a sequence that is partially complementary to the fifth oligonucleotide, but the fifth oligonucleotide is preferably an oligonucleotide that does not contain a sequence that is partially complementary to the fifth oligonucleotide. Examples of groups derived from such oligonucleotides include (N) linked by a phosphodiester bond. k (Each N is independently adenosine, uridine, cytidine, guanosine, 2'-deoxyadenosine, thymidine, 2'-deoxycytidine, or 2'-deoxyguanosine, and k is an integer (repetition number) of 1 to 40. Among these, k is preferably 3 to 20, more preferably 4 to 10, even more preferably 4 to 7, still more preferably 4 or 5, and particularly preferably 4. The same applies to the sixth and seventh oligonucleotides as to the fifth oligonucleotide. In another embodiment, k is preferably 2 to 5, more preferably 2 to 4, for the sixth and seventh oligonucleotides.

[0238] When the single-stranded oligonucleotide of the present invention has a group derived from a fifth oligonucleotide and a group derived from a sixth oligonucleotide, the fifth oligonucleotide may have the same sequence as the sixth oligonucleotide or may have a different sequence. When the single-stranded oligonucleotide of the present invention has a group derived from a fifth oligonucleotide and a group derived from a seventh oligonucleotide, the fifth oligonucleotide may have the same sequence as the seventh oligonucleotide or may have a different sequence. When the single-stranded oligonucleotide of the present invention has a group derived from the sixth oligonucleotide and a group derived from the seventh oligonucleotide, the sixth oligonucleotide may have the same sequence as the seventh oligonucleotide or may have a different sequence. In addition, the sixth oligonucleotide and the seventh oligonucleotide may or may not hybridize intramolecularly, but preferably hybridize intramolecularly.

[0239] A functional molecule may be bound directly or indirectly to X, Y, Xz, Yz, L, Lx, and Ly. When at least one of X (a group derived from the first oligonucleotide) and Xz (a group derived from the third oligonucleotide) contains an antisense sequence portion, the functional molecule is preferably bound to the second or fourth oligonucleotide. The functional molecule may be bound to the second or fourth oligonucleotide directly or indirectly via another substance. However, it is preferred that the second or fourth oligonucleotide and the functional molecule are bound to each other via a covalent bond, an ionic bond, or a hydrogen bond. From the viewpoint of high bond stability, a direct covalent bond or a covalent bond via a linker (linking group) is more preferred. When Yz (the fourth oligonucleotide) contains an antisense sequence portion, the functional molecule is preferably bound to the first or third oligonucleotide. The bond between the functional molecule and the first or third oligonucleotide is similar to the bond between the functional molecule and the second or fourth oligonucleotide. When the first and fourth oligonucleotides each contain an antisense sequence portion, the functional molecule is preferably bound to the third oligonucleotide. The binding between the functional molecule and the first to fourth oligonucleotides is the same as described above.

[0240] When the functional molecule is covalently bound to the single-stranded oligonucleotide, the functional molecule is preferably bound directly or indirectly to the 3'-end or 5'-end of the single-stranded oligonucleotide. The bond between the linker or functional molecule and the terminal nucleotide of the single-stranded oligonucleotide is selected depending on the functional molecule. The linker or functional molecule and the terminal nucleotide of the single-stranded oligonucleotide molecule are preferably linked via a phosphodiester bond or a modified phosphodiester bond, more preferably via a phosphodiester bond. The linker or functional molecule may be directly linked to the 3'-position oxygen atom of the 3'-terminal nucleotide or the 5'-position oxygen atom of the 5'-terminal nucleotide of the single-stranded oligonucleotide molecule.

[0241] In another embodiment, the functional molecule is preferably directly or indirectly bound to L. In this case, L is preferably a linking group containing a non-nucleotide structure, and particularly preferably a linking group represented by the following formula: [ka] {where, V 12 teeth, C 2-20 Alkylene group (the C 2-20 The alkylene group is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy groups and amino groups; The following formula (VIII-2, 3, 9 or 11): [ka] (In the formula, о 1 is an integer between 0 and 10, and p 1 is an integer between 0 and 10, and d 1 is an integer between 1 and 10) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 12 is C 2-20 Alkylene group (the C 2-20 the alkylene group is substituted with one or more substituents selected from the group consisting of a hydroxy group and an amino group), or a group selected from the formula (VIII-2, 3, 9 or 11), P 12 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 12 is -P(=O)(OH)-, q7 is an integer of 1 to 10, q8 is an integer of 1 to 6, and when at least one of q7 and q8 is 2 or more, V 12 are the same or different}, and a group represented by the following formula: [ka] (wherein each s is independently an integer of 1 to 10) is more preferred, and a group represented by the following formula: [ka] A group represented by the following formula is particularly preferred.

[0242] In another embodiment, the linking group containing a non-nucleotide structure in L when the functional molecule is bound to L is The following formula: [ka] {where, V 12 teeth, The following formula (XVIII-11): [ka] a group represented by a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 12 is a group represented by the formula (XVIII-11), P 12 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 12 is -P(=O)(OH)-, q7 is 1, q8 is an integer from 1 to 6, and when q8 is 2 or more, V 12 are the same or different}, and The following formula: [ka] {where, V 12 teeth, The following formula (XVIII-12): [ka] a group represented by a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 12 is a group represented by the formula (XVIII-12), P 12 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 12 is -P(=O)(OH)-, q7 is 1, q8 is an integer from 1 to 6, and when q8 is 2 or more, V 12 are the same or different}, The following formula: [ka] {where, V 12 teeth, The following formula (XVIII-12): [ka] a group represented by a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 12 is a group represented by the formula (XVIII-12), q8 is an integer from 1 to 6, and when q8 is 2 or more, V 12 are the same or different} are more preferred.

[0243] When a functional molecule is directly or indirectly bound to L, which is a linking group containing a non-nucleotide structure, the functional molecule may replace a hydrogen atom at any part of the linking group containing a non-nucleotide structure described above and be directly or indirectly bound to the corresponding carbon atom, nitrogen atom, oxygen atom, etc. For example, when the linking group containing a non-nucleotide structure is represented by the formula: [ka] In the case where the linking group is a group represented by the formula (XIII-2, 3, 9, or 11), a functional molecule may be bonded to Rc in the formula (XIII-2, 3, 9, or 11), or a linking group described below may be bonded to Rc, and the functional molecule may be bonded to the linking group. Furthermore, a functional molecule may be bonded to an alkylene group, a ribonucleoside group, a deoxyribonucleoside group, or the like, with or without a linking group. When L, which is a linking group containing a non-nucleotide structure, has an amino group or a hydroxy group, the functional molecule is preferably bonded directly or indirectly via a linking group to the nitrogen atom of the amino group (-NH, -NH-, etc.) or the oxygen atom of the hydroxy group of the linking group containing a non-nucleotide structure.

[0244] The structure of the "functional molecule" is not particularly limited, and its binding confers a desired function to the single-stranded oligonucleotide. Desired functions include labeling, purification, and delivery to a target site. Examples of molecules that impart a labeling function include compounds such as fluorescent proteins and luciferase. Examples of molecules that impart a purification function include compounds such as biotin, avidin, His tag peptide, GST tag peptide, and FLAG tag peptide.

[0245] Furthermore, from the viewpoint of highly specific and efficient delivery of single-stranded oligonucleotides to target sites (e.g., target cells) and highly effective control of target gene expression by the single-stranded oligonucleotides, it is preferable that the functional molecule be a molecule capable of delivering the single-stranded oligonucleotide to the target site. For details of molecules with delivery functionality, see, for example, European Journal of Pharmaceuticals and Biopharmaceutics, Vol. 107, pp. 321-340 (2016); Advanced Drug Delivery Reviews, Vol. 104, pp. 78-92 (2016); and Expert Opinion on Drug Delivery, Vol. 11, pp. 791-822 (2014).

[0246] Molecules that impart a delivery function to target RNA include, for example, lipids and sugars, which can deliver single-stranded oligonucleotides to the liver and other organs with high specificity and efficiency. Examples of such lipids include cholesterol; fatty acids; fat-soluble vitamins such as vitamin E (tocopherols and tocotrienols), vitamin A, vitamin D, and vitamin K; intermediate metabolites such as acylcarnitine and acyl-CoA; glycolipids; glycerides; and derivatives thereof. Among these, cholesterol and vitamin E (tocopherols and tocotrienols) are preferred from the viewpoint of higher safety. Among these, tocopherols are more preferred, tocopherol is even more preferred, and α-tocopherol is particularly preferred. Examples of sugars include sugar derivatives that interact with the asialoglycoprotein receptor.

[0247] The "asialoglycoprotein receptor" is present on the surface of liver cells and recognizes the galactose residue of asialoglycoprotein, taking up the molecule into the cell and degrading it. The "sugar derivative that interacts with the asialoglycoprotein receptor" is preferably a compound that has a structure similar to that of a galactose residue and is taken up into the cell through interaction with the asialoglycoprotein receptor, such as GalNAc (N-acetylgalactosamine) derivatives, galactose derivatives, and lactose derivatives. From the perspective of being able to deliver the single-stranded oligonucleotide of the present invention to the brain with high specificity and efficiency, the "functional molecule" may be a sugar (e.g., glucose, sucrose, etc.). From the perspective of being able to deliver the single-stranded oligonucleotide to each organ with high specificity and efficiency by interacting with various proteins on the cell surface of the organ, the "functional molecule" may be a receptor ligand, an antibody, or a peptide or protein fragment thereof.

[0248] The linker connecting the functional molecule to X, Y, Xz, Yz, L, Lx, or Ly is not particularly limited as long as it can stably bond the functional molecule to the oligonucleotide, as long as it can exhibit the function of the functional molecule as a single-stranded oligonucleotide molecule. Examples of the linker include a group derived from an oligonucleotide having 2 to 20 nucleotides, a group derived from a polypeptide having 2 to 20 amino acids, an alkylene group having 2 to 20 carbon atoms, and an alkenylene group having 2 to 20 carbon atoms. The group derived from an oligonucleotide having 2 to 20 nucleotides is a group obtained by removing a hydroxy group, a hydrogen atom, or the like from an oligonucleotide having 2 to 20 nucleotides. The group derived from a polypeptide having 2 to 20 amino acids is a group obtained by removing a hydroxy group, a hydrogen atom, an amino group, or the like from a polypeptide having 2 to 20 amino acids. Furthermore, the structure of the linker can be found in articles such as European Journal of Pharmaceuticals and Biopharmaceutics, Vol. 107, pp. 321-340 (2016), Advanced Drug Delivery Reviews, Vol. 104, pp. 78-92 (2016), Expert Opinion on Drug Delivery, Vol. 11, pp. 791-822 (2014), and Journal of Medicinal Chemistry, Vol. 59, p. 2718 (2016), as well as materials indexed in these articles.

[0249] The linker is preferably C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or two substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6In this case, the linker is -C(=O)-O-, -OC(=O)-NR-, -C ... 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 (representing an alkyl group), -C(=O)-NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 (representing an alkyl group), -C(=S)-NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 (representing an alkyl group), -NR 1 -C(=O)-NR 1 -(R 1 are each independently a hydrogen atom, C 1-6 Alkyl or haloC 1-6 It may contain a group represented by the formula (representing an alkyl group).

[0250] The linker is more preferably C 2-20 alkylene groups (each methylene group of the alkylene group is independently unsubstituted or replaced by -O-; each unsubstituted methylene group is independently unsubstituted or substituted by a hydroxy group or a protected hydroxy group), more preferably C 8-12 The linker is preferably an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and particularly preferably a 1,8-octylene group. In another embodiment, the linker is particularly preferably a group represented by the following formula (III):

[0251] [ka]

[0252] In the formula, one * represents the bonding position with the group derived from the oligonucleotide (an atom constituting the nucleotide), and the other * represents the bonding position with the group derived from the functional molecule (an atom constituting the group derived from the functional molecule).

[0253] In another embodiment, the linker is more preferably C 2-20 an alkylene group, wherein each methylene group of the alkylene group is independently unsubstituted or is —O— or —NR B -(R B is a hydrogen atom or C 1-6 The unsubstituted methylene groups are each independently unsubstituted or substituted with an oxo group), and more preferably, the methylene groups are represented by the following formula: [ka] (wherein each e is independently an integer of 1 to 6), and particularly preferably a group represented by the following formula: [ka] It is a group represented by the formula:

[0254] In another embodiment, the linker is more preferably The following formula: [ka] (In the ceremony e2 is an integer of 1 to 20), and even more preferably a group represented by the following formula: [ka] (In the ceremony e2 is an integer of 2 to 10), and particularly preferably, The following formula: [ka] It is a group represented by the formula:

[0255] In another embodiment, the linker is more preferably of the formula: [ka] (In the ceremony e4 is an integer between 1 and 20, e5 is an integer of 0 to 10), or a group represented by the following formula: [ka] (In the ceremony e6 is an integer between 1 and 20, e7 is an integer from 0 to 10) is.

[0256] The protecting group for the "protected hydroxy group" is not particularly limited as long as it is stable when the functional molecule and the oligonucleotide are linked. The linker is not particularly limited, and examples thereof include any protecting group described in, for example, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons (1999). Specific examples include methyl, benzyl, p-methoxybenzyl, t-butyl, methoxymethyl, methoxyethyl, 2-tetrahydropyranyl, ethoxyethyl, cyanoethyl, cyanoethoxymethyl, phenylcarbamoyl, 1,1-dioxothiomorpholine-4-thiocarbamoyl, acetyl, pivaloyl, benzoyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl. Examples of such groups include a methyl group, a [(triisopropylsilyl)oxy]methyl group (Tom group), a 1-(4-chlorophenyl)-4-ethoxypiperidin-4-yl group (Cpep group), a triphenylmethyl group (trityl group), a monomethoxytrityl group, a dimethoxytrityl group (DMTr group), a trimethoxytrityl group, a 9-phenylxanthen-9-yl group (Pixyl group), and a 9-(p-methoxyphenyl)xanthen-9-yl group (MOX group). The protecting group for the "protected hydroxy group" is preferably a benzoyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, a triphenylmethyl group, a monomethoxytrityl group, a dimethoxytrityl group, a trimethoxytrityl group, a 9-phenylxanthen-9-yl group, or a 9-(p-methoxyphenyl)xanthen-9-yl group, more preferably a monomethoxytrityl group, a dimethoxytrityl group, or a trimethoxytrityl group, and even more preferably a dimethoxytrityl group.

[0257] The bond between the group derived from the functional molecule and the linker is preferably a covalent bond, more preferably an ether bond or an amide bond. An ether bond can be formed, for example, by reacting a hydroxy group of a group derived from a functional molecule with a linker having a leaving group. The "leaving group" includes acetate, p-nitrobenzoate, sulfonate (e.g., methanesulfonate, p-toluenesulfonate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, fluoromethanesulfonate, difluoromethanesulfonate, trifluoromethanesulfonate, ethanesulfonate, etc.), amino, halide ester, and halogen ion (e.g., I - , Br - , Cl - ) and hydroxy, but are not limited to these. Depending on the structure of the leaving group, a base may be added as appropriate. The base to be used is not particularly limited. Examples include organic bases such as triethylamine, tributylamine, N,N-diisopropylethylamine, pyridine, and DBU; inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, and potassium hydroxide; and organometallic compounds such as butyllithium and phenyllithium. An amide bond can be formed, for example, by reacting an amino group of a functional molecule-derived group with a linker having a carboxylic acid, ester, activated ester (e.g., N-hydroxysuccinimide), acid chloride, activated carbonate diester (e.g., 4-nitrophenyl carbonate diester), isocyanate, or the like. Specific reaction conditions for the formation of the ether bond and the amide bond can be found in, for example, Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, Inc. A conjugate of a functional group and a linker can be synthesized by the methods described in these known documents, methods based thereon, or a combination of these with conventional methods. Furthermore, for other embodiments of methods for bonding functional groups to linkers, reference can be made to articles described in European Journal of Pharmaceuticals and Biopharmaceutics, Vol. 107, pp. 321-340 (2016), Advanced Drug Delivery Reviews, Vol. 104, pp. 78-92 (2016), Expert Opinion on Drug Delivery, Vol. 11, pp. 791-822 (2014), and Journal of Medicinal Chemistry, Vol. 59, p. 2718 (2016), as well as materials indexed in these articles.

[0258] Preferred single-stranded oligonucleotides for use in nucleic acid drugs include those shown below. 1) The following formula (I) [ka] wherein X is a group derived from a first oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and including at least one nucleotide in which at least one of the sugar moiety, the base moiety, and the phosphate moiety has been modified; Y is a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one ribonucleotide; Xz is a group derived from a third oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and including at least one nucleotide in which at least one of the sugar moiety, base moiety, and phosphate moiety has been modified; Yz is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and including at least one nucleotide in which at least one of the sugar moiety, base moiety, and phosphate moiety has been modified; L is Linking groups containing non-nucleotide structures, or of the formula: [ka] (In the formula, W 5 is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), Lx is -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or a group represented by the following formula: [ka] (In the formula, W 6 is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), Ly is a linking group containing -P(=O)(OH)-, a non-nucleotide structure, or the formula: [ka] (In the formula, W 7is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), at least one of L, Lx, and Ly is a linking group containing the non-nucleotide structure; L is covalently bonded at both ends to the first oligonucleotide and the second oligonucleotide, respectively; Lx is covalently bound to the first oligonucleotide and the third oligonucleotide at both ends thereof, Ly is covalently bound at both ends to the second oligonucleotide and the fourth oligonucleotide, respectively; m and n each independently represent 0 or 1; the first oligonucleotide has a nucleotide sequence X, the second oligonucleotide has a nucleotide sequence Y, the third oligonucleotide has a nucleotide sequence Xz, and the fourth oligonucleotide has a nucleotide sequence Yz; the nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing to at least a portion of a second oligonucleotide; the nucleotide sequence Y comprises a second nucleotide sequence capable of hybridizing to at least a portion of the first oligonucleotide and comprising at least one ribonucleotide; At least one of the nucleotide sequence X, the nucleotide sequence Xz, and the nucleotide sequence Yz comprises an antisense sequence capable of hybridizing with a target RNA; When there are two or more antisense sequences, the target RNAs to which the respective antisense sequence portions hybridize may be the same or different. wherein X and Y hybridize at the first nucleotide sequence portion and the second nucleotide sequence portion.

[0259] 2) The single-stranded oligonucleotide according to 1), wherein X is bound to L on the 3' side and Y is bound to L on the 5' side. 3) The single-stranded oligonucleotide according to 1), wherein X is bound to L on the 5' side and Y is bound to L on the 3' side.

[0260] 4) The single-stranded oligonucleotide according to any one of 1) to 3), wherein the complementarity between the antisense sequence and the sequence of the target RNA is 70% or more. 5) The single-stranded oligonucleotide according to any one of 1) to 4), wherein the complementarity between the first nucleotide sequence and the second nucleotide sequence is 70% or more.

[0261] 6) The nucleotides contained in X are linked to each other by at least one bond independently selected from the group consisting of a phosphodiester bond, a phosphorothioate bond, a methylphosphonate bond, a methylthiophosphonate bond, a phosphorodithioate bond, and a phosphoramidate bond; the nucleotides contained in Y are linked to each other by at least one bond independently selected from the group consisting of a phosphodiester bond, a phosphorothioate bond, a methylphosphonate bond, a methylthiophosphonate bond, a phosphorodithioate bond, and a phosphoramidate bond; and the nucleotides contained in Xz are linked to each other by at least one bond independently selected from the group consisting of a phosphodiester bond, a phosphorothioate bond, a methylphosphonate bond, a methylthiophosphonate bond, a phosphorodithioate bond, and a phosphoramidate bond; 5) The single-stranded oligonucleotide according to any one of 1) to 5), wherein the nucleotides in Yz are linked to each other by at least one bond independently selected from the group consisting of a phosphodiester bond, a phosphorothioate bond, a methylphosphonate bond, a methylthiophosphonate bond, a phosphorodithioate bond, and a phosphoramidate bond, and the nucleotides in Yz are linked to each other by at least one bond independently selected from the group consisting of a phosphodiester bond, a phosphorothioate bond, a methylphosphonate bond, a methylthiophosphonate bond, a phosphorodithioate bond, and a phosphoramidate bond. 7) The single-stranded oligonucleotide according to any one of 1) to 6), wherein the nucleotides contained in X are linked to each other by at least one bond independently selected from a phosphodiester bond and a phosphorothioate bond, the nucleotides contained in Y are linked to each other by at least one bond independently selected from a phosphodiester bond and a phosphorothioate bond, the nucleotides contained in Xz are linked to each other by at least one bond independently selected from a phosphodiester bond and a phosphorothioate bond, and the nucleotides contained in Yz are linked to each other by at least one bond independently selected from a phosphodiester bond and a phosphorothioate bond.

[0262] 8) A single-stranded oligonucleotide according to any one of 1) to 7), wherein the first oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the first nucleotide sequence portion. 9) The single-stranded oligonucleotide according to any one of 1) to 8), wherein the first oligonucleotide comprises a phosphorothioate bond. 10) A single-stranded oligonucleotide according to any one of 1) to 9), wherein the first nucleotide sequence is a sequence comprising nucleotides linked to each other by phosphorothioate bonds. 11) The single-stranded oligonucleotide according to any one of 1) to 10), wherein the nucleotides contained in the first oligonucleotide are linked to each other by phosphorothioate bonds. 12) The single-stranded oligonucleotide according to any one of 1) to 11), wherein the first nucleotide sequence is a sequence consisting of 4 to 30 nucleotides independently selected from sugar-modified nucleotides and deoxyribonucleotides. 13) The single-stranded oligonucleotide according to any one of 1) to 12), wherein the first nucleotide sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

[0263] 14) The single-stranded oligonucleotide according to any one of 1) to 13), wherein the first nucleotide sequence is a sequence consisting of 4 to 20 deoxyribonucleotides. 15) The single-stranded oligonucleotide according to any one of 1) to 14), wherein the first nucleotide sequence is a sequence containing at least four consecutive nucleotides that are recognized by RNase H. 16) A single-stranded oligonucleotide according to any one of 1) to 15), wherein the first nucleotide sequence is a sequence containing at least four consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA.

[0264] 17) A single-stranded oligonucleotide according to any one of 1) to 13), wherein the first nucleotide sequence portion contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. 18) The single-stranded oligonucleotide according to 17), wherein at least one of the 3'-nucleotide and the 5'-nucleotide of the first nucleotide sequence portion is a sugar-modified nucleotide. 19) The single-stranded oligonucleotide according to 17) or 18), wherein the nucleotide on the 3' side and the 5' side of the first nucleotide sequence portion are sugar-modified nucleotides. 20) The single-stranded oligonucleotide according to any one of 1) to 12), wherein the first nucleotide sequence is a sequence consisting of 4 to 30 sugar-modified nucleotides.

[0265] 21) A single-stranded oligonucleotide according to any one of 1) to 20), wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the first nucleotide sequence portion. 22) The single-stranded oligonucleotide according to any one of 1) to 21), wherein X comprises at least one sugar-modified nucleotide.

[0266] 23) The single-stranded oligonucleotide according to any one of 1) to 22), wherein the second nucleotide sequence is a sequence containing at least four consecutive nucleotides that are cleaved by RNase H. 24) The single-stranded oligonucleotide according to any one of 1) to 23), wherein the second nucleotide sequence is a sequence consisting of 4 to 25 ribonucleotides. 25) A single-stranded oligonucleotide according to any one of 1) to 24), wherein the second oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the second nucleotide sequence portion. 26) The single-stranded oligonucleotide according to any one of 1) to 25), wherein the second oligonucleotide comprises a phosphodiester bond. 27) A single-stranded oligonucleotide according to any one of 1) to 26), wherein at least one of the 5' and 3' ends of the second nucleotide sequence portion is linked to an adjacent nucleotide via a phosphodiester bond. 28) The single-stranded oligonucleotide according to any one of 1) to 27), wherein the second nucleotide sequence is a sequence comprising nucleotides linked to each other by phosphodiester bonds.

[0267] 29) The single-stranded oligonucleotide according to any one of 1) to 28), wherein nucleotide sequence X comprises at least one antisense sequence and the first nucleotide sequence is the antisense sequence.

[0268] 30) The single-stranded oligonucleotide according to 29), wherein m is 0 and n is 0. 31) The single-stranded oligonucleotide according to 30), wherein at least one of the 5' and 3' ends of the second nucleotide sequence portion is linked to an adjacent nucleotide via a phosphorothioate bond.

[0269] 32) The single-stranded oligonucleotide according to any one of 1) to 29), wherein m is 1 and the nucleotide sequence Xz comprises at least one antisense sequence.

[0270] 33) The single-stranded oligonucleotide according to 32), wherein the antisense sequence portion contained in Xz contains a phosphorothioate bond. 34) The single-stranded oligonucleotide according to 32) or 33), wherein the antisense sequence contained in the nucleotide sequence Xz is a sequence containing nucleotides linked to each other via phosphorothioate bonds. 35) The single-stranded oligonucleotide according to any one of 32) to 34), wherein the nucleotides contained in the third oligonucleotide are linked to each other by phosphorothioate bonds.

[0271] 36) The single-stranded oligonucleotide according to any one of 32) to 35), wherein the third oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the antisense sequence portion contained in Xz. 37) The single-stranded oligonucleotide according to any one of 32) to 36), wherein the third oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the antisense sequence portion contained in Xz. 38) The single-stranded oligonucleotide according to 36) or 37), wherein the sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' ends of the antisense sequence portion contained in Xz is linked to at least one of the 5' and 3' ends of the antisense sequence portion contained in Xz via a phosphorothioate bond.

[0272] 38) The single-stranded oligonucleotide according to any one of 32) to 37), wherein the antisense sequence contained in the nucleotide sequence Xz is a sequence consisting of 4 to 30 nucleotides independently selected from sugar-modified nucleotides and deoxyribonucleotides. 39) The single-stranded oligonucleotide according to any one of 32) to 38), wherein the antisense sequence contained in the nucleotide sequence Xz is a sequence consisting of 4 to 20 nucleotides containing at least one deoxyribonucleotide.

[0273] 40) The single-stranded oligonucleotide according to any one of 32) to 39), wherein the antisense sequence contained in the nucleotide sequence Xz is a sequence containing at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA. 41) The single-stranded oligonucleotide according to any one of 32) to 40), wherein the antisense sequence contained in the nucleotide sequence Xz is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0274] 42) A single-stranded oligonucleotide according to any one of 32) to 39), wherein the antisense sequence portion contained in Xz contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. 43) The single-stranded oligonucleotide according to 42), wherein at least one of the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in Xz is a sugar-modified nucleotide. 44) The single-stranded oligonucleotide according to 42) or 43), wherein the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in Xz are sugar-modified nucleotides. 45) The single-stranded oligonucleotide according to any one of 32) to 38), wherein the antisense sequence contained in the nucleotide sequence Xz is a sequence consisting of 4 to 30 sugar-modified nucleotides.

[0275] 46) The single-stranded oligonucleotide according to any one of 32) to 45), wherein Lx and L are each independently a linking group containing a non-nucleotide structure. 47) Lx is a linking group containing a non-nucleotide structure, L is a group having the following formula: [ka] (In the formula, W 5is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides). 48) X and Xz are directly linked via a phosphodiester bond, The single-stranded oligonucleotide according to any one of 32) to 45), wherein L is a linking group containing a non-nucleotide structure. 49) Lx is a compound having the following formula: [ka] (In the formula, W 6 is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), The single-stranded oligonucleotide according to any one of 32) to 45), wherein L is a linking group containing a non-nucleotide structure.

[0276] 50) The single-stranded oligonucleotide according to any one of 32) to 49), wherein n is 0. 51) The single-stranded oligonucleotide according to 50), wherein at least one of the 5' and 3' ends of the second nucleotide sequence portion is linked to an adjacent nucleotide via a phosphorothioate bond.

[0277] 52) The single-stranded oligonucleotide according to any one of 32) to 49), wherein n is 1, the nucleotide sequence Yz comprises a fourth nucleotide sequence capable of hybridizing to at least a portion of the antisense sequence portion comprised by Xz, and the fourth nucleotide sequence comprises at least one ribonucleotide. 53) The single-stranded oligonucleotide according to 52), wherein the 5' and 3' ends of the second nucleotide sequence portion are linked to adjacent groups via phosphodiester bonds.

[0278] 54) The single-stranded oligonucleotide according to 52) or 53), wherein the fourth nucleotide sequence is a sequence containing at least four consecutive nucleotides that are cleaved by RNase H. 55) The single-stranded oligonucleotide according to any one of 52) to 54), wherein the fourth nucleotide sequence is a sequence consisting of 4 to 20 ribonucleotides. 56) A single-stranded oligonucleotide according to any one of 52) to 55), wherein the fourth oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the fourth nucleotide sequence portion. 57) A single-stranded oligonucleotide according to any one of 52) to 56), wherein at least one of the 5' and 3' ends of the fourth nucleotide sequence portion is linked to an adjacent nucleotide via a phosphorothioate bond.

[0279] 58) A single-stranded oligonucleotide according to any one of 52) to 57), wherein Y and Yz are directly linked via a phosphodiester bond. 59) Ly has the formula: [ka] (In the formula, W 7 is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides). 60) The single-stranded oligonucleotide according to any one of 52) to 57), wherein Ly is a linking group containing a non-nucleotide structure.

[0280] 61) The single-stranded oligonucleotide according to any one of 1) to 29), wherein n is 1 and the nucleotide sequence Yz includes at least one antisense sequence.

[0281] 62) The single-stranded oligonucleotide according to 61), wherein the 5' and 3' ends of the second nucleotide sequence portion are linked to adjacent groups via phosphodiester bonds.

[0282] 63) The single-stranded oligonucleotide according to 61) or 62), wherein the antisense sequence portion contained in Yz contains a phosphorothioate bond. 64) The single-stranded oligonucleotide according to any one of 61) to 63), wherein the antisense sequence portion contained in Yz is a sequence containing nucleotides linked to each other via phosphorothioate bonds. 65) A single-stranded oligonucleotide according to any one of 61) to 64), wherein the nucleotides contained in the fourth oligonucleotide are linked to each other by phosphorothioate bonds.

[0283] 66) A single-stranded oligonucleotide according to any one of 61) to 65), wherein the fourth oligonucleotide comprises a sugar-modified nucleotide attached adjacent to at least one of the 5' and 3' sides of the antisense sequence portion contained in Yz. 67) A single-stranded oligonucleotide according to any one of 61) to 66), wherein the fourth oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the antisense sequence portion contained in Yz. 68) A single-stranded oligonucleotide according to 66) or 67), wherein the sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' ends of the antisense sequence portion contained in Yz is linked to at least one of the 5' and 3' ends of the antisense sequence portion contained in Yz via a phosphorothioate bond.

[0284] 68) The single-stranded oligonucleotide according to any one of 61) to 67), wherein the antisense sequence contained in the nucleotide sequence Yz is a sequence consisting of 4 to 30 nucleotides independently selected from sugar-modified nucleotides and deoxyribonucleotides. 69) A single-stranded oligonucleotide according to any one of 61) to 68), wherein the antisense sequence contained in Yz is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

[0285] 70) A single-stranded oligonucleotide according to any one of 61) to 69), wherein the antisense sequence contained in the nucleotide sequence Yz is a sequence containing at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA. 71) The single-stranded oligonucleotide according to any one of 61) to 70), wherein the antisense sequence contained in Yz is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0286] 72) A single-stranded oligonucleotide according to any one of 61) to 69), wherein the antisense sequence portion contained in Yz contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. 73) The single-stranded oligonucleotide according to 72), wherein at least one of the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in Yz is a sugar-modified nucleotide. 74) The single-stranded oligonucleotide according to 72) or 73), wherein the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in Yz are sugar-modified nucleotides. 75) The single-stranded oligonucleotide according to any one of 61) to 68), wherein the antisense sequence contained in the nucleotide sequence Yz is a sequence consisting of 4 to 30 sugar-modified nucleotides.

[0287] 76) The single-stranded oligonucleotide according to any one of 61) to 75), wherein Ly and L are each independently a linking group containing a non-nucleotide structure. 77) Ly is a linking group containing a non-nucleotide structure; L is a group having the following formula: [ka] (In the formula, W 5 is a group derived from a fifth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides). 78) Y and Yz are directly linked via a phosphodiester bond; The single-stranded oligonucleotide according to any one of 61) to 75), wherein L is a linking group containing a non-nucleotide structure. 79) Ly has the formula: [ka] (In the formula, W 7 is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides), The single-stranded oligonucleotide according to any one of 61) to 75), wherein L is a linking group containing a non-nucleotide structure.

[0288] 80) The single-stranded oligonucleotide according to any one of 61) to 79), wherein m is 0. 81) A single-stranded oligonucleotide according to any one of 61) to 79), wherein m is 1, the nucleotide sequence Xz comprises a third nucleotide sequence capable of hybridizing with at least a portion of the antisense sequence portion comprised by Yz, and the third nucleotide sequence comprises at least one ribonucleotide. 82) The single-stranded oligonucleotide according to 81), wherein the third nucleotide sequence is a sequence containing at least four consecutive nucleotides that are cleaved by RNase H. 83) The single-stranded oligonucleotide according to 81) or 82), wherein the third nucleotide sequence is a sequence consisting of 4 to 20 ribonucleotides. 84) A single-stranded oligonucleotide according to any one of 81) to 83), wherein the third oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the third nucleotide sequence portion. 85) A single-stranded oligonucleotide according to any one of 81) to 84), wherein at least one of the 5' and 3' ends of the third nucleotide sequence portion is linked to an adjacent nucleotide via a phosphorothioate bond.

[0289] 86) A single-stranded oligonucleotide according to any one of 81) to 85), wherein Y and Yz are directly linked via a phosphodiester bond. 87) Lx is a compound having the following formula: [ka] (In the formula, W 6 is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides). 88) The single-stranded oligonucleotide according to any one of 81) to 85), wherein Lx is a linking group containing a non-nucleotide structure.

[0290] 89) The linking groups containing a non-nucleotide structure are each independently represented by the following formula: [ka] {where, V 0 teeth, C 2-50 Alkylene group (the C 2-50 The alkylene group may be unsubstituted or may be selected from the group consisting of the substituents V a and substituted with one or more substituents independently selected from the group consisting of: Substituent group V ameans a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, q1 is an integer of 1 to 10, q2 is an integer of 1 to 20, and when at least one of q1 and q2 is 2 or more, V 0 The single-stranded oligonucleotide according to any one of 1) to 88), wherein: is a group represented by the formula {which may be the same or different}.

[0291] 90) The single-stranded oligonucleotide according to any one of 1) to 29), wherein the fifth oligonucleotide comprises a phosphodiester bond. 91) The single-stranded oligonucleotide according to 90), wherein the nucleotides contained in the fifth oligonucleotide are linked to each other by phosphodiester bonds. 92) The single-stranded oligonucleotide according to 90) or 91), wherein the fifth oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 93) A single-stranded oligonucleotide according to any one of 90) to 92), wherein the fifth oligonucleotide consists of 4 to 7 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 94) The single-stranded oligonucleotide according to any one of 90) to 93), wherein the fifth oligonucleotide is an oligodeoxyribonucleotide or an oligoribonucleotide. 95) The single-stranded oligonucleotide according to any one of 90) to 94), wherein the fifth oligonucleotide is DNA or RNA. 96) The single-stranded oligonucleotide according to any one of 90) to 95), wherein the fifth oligonucleotide is RNA.

[0292] 97) The single-stranded oligonucleotide according to any one of 1) to 29), wherein the sixth oligonucleotide comprises a phosphodiester bond. 98) The single-stranded oligonucleotide according to 97), wherein the nucleotides contained in the sixth oligonucleotide are linked to each other by phosphodiester bonds. 99) The single-stranded oligonucleotide according to any one of 97) or 98), wherein the sixth oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 100) The single-stranded oligonucleotide according to any one of 97) to 99), wherein the sixth oligonucleotide consists of 4 to 7 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 101) The single-stranded oligonucleotide according to any one of 97) to 100), wherein the sixth oligonucleotide is an oligodeoxyribonucleotide or an oligoribonucleotide. 102) The single-stranded oligonucleotide according to any one of 97) to 101), wherein the sixth oligonucleotide is DNA or RNA. 103) The single-stranded oligonucleotide according to any one of 97) to 102), wherein the sixth oligonucleotide is RNA.

[0293] 104) The single-stranded oligonucleotide according to any one of 1) to 29), wherein the seventh oligonucleotide comprises a phosphodiester bond. 105) The single-stranded oligonucleotide according to 104), wherein the nucleotides contained in the seventh oligonucleotide are linked to each other by phosphodiester bonds. 107) The single-stranded oligonucleotide according to 104) or 105), wherein the seventh oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 108) The single-stranded oligonucleotide according to any one of 104) to 107), wherein the seventh oligonucleotide consists of 4 to 7 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 109) The single-stranded oligonucleotide according to any one of 104) to 108), wherein the seventh oligonucleotide is an oligodeoxyribonucleotide or an oligoribonucleotide. 110) The single-stranded oligonucleotide according to any one of 104) to 109), wherein the seventh oligonucleotide is DNA or RNA. 111) The single-stranded oligonucleotide according to any one of 104) to 110), wherein the seventh oligonucleotide is RNA.

[0294] 112) The single-stranded oligonucleotide according to any one of 1) to 111), wherein the sugar-modified nucleotides are each independently a 2'-O-methylated nucleotide, a 2'-O-methoxyethylated nucleotide, a 2'-O-aminopropylated nucleotide, a 2'-fluorolated nucleotide, a 2'-F-arabinonucleotide, a bridged nucleotide, or a 2'-O-methylcarbamoylethylated nucleotide. 113) The single-stranded oligonucleotide according to any one of 1) to 112), wherein the sugar-modified nucleotides are each independently a 2'-O-methylated nucleotide, a 2'-O-methylcarbamoylethylated nucleotide, or an LNA. 114) The single-stranded oligonucleotide according to any one of 1) to 113), wherein the sugar-modified nucleotides are each independently a 2'-O-methylated nucleotide or an LNA.

[0295] 115) A single-stranded oligonucleotide according to any one of 1) to 114), further comprising a group derived from a functional molecule having at least one function selected from the group consisting of a labeling function, a purification function, and a delivery function to a target RNA. 116) The single-stranded oligonucleotide according to 115), wherein the group derived from the functional molecule is directly or indirectly bound to the 5'-terminal nucleotide of the single-stranded oligonucleotide represented by formula (I). 117) The single-stranded oligonucleotide according to 115), wherein the group derived from the functional molecule is directly or indirectly bound to the 3'-terminal nucleotide of the single-stranded oligonucleotide represented by formula (I). 118) The single-stranded oligonucleotide according to 115), wherein the group derived from the functional molecule is directly or indirectly bound to L.

[0296] 119) The group derived from the functional molecule is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 The single-stranded oligonucleotide according to any one of 115) to 118), which is bonded to the single-stranded oligonucleotide represented by formula (I) via a -S-, -S(=O)- or -S(=O)2- group (which is an alkyl group), or by a direct covalent bond. 120) C to which a group derived from the functional molecule is linked 2-20 Alkylene group or C 2-20 The single-stranded oligonucleotide according to any one of 115) to 117), wherein the alkenylene group and the 5'-terminal or 3'-terminal nucleotide of the single-stranded oligonucleotide represented by formula (I) are linked via a phosphodiester bond or a modified phosphodiester bond. 121) C to which a group derived from the functional molecule is linked 2-20 Alkylene group or C 2-20 The single-stranded oligonucleotide according to any one of 115) to 117), wherein the alkenylene group and the 5'-terminal or 3'-terminal nucleotide of the single-stranded oligonucleotide represented by formula (I) are linked via a phosphodiester bond. 122) The single-stranded oligonucleotide according to any one of 115) to 121), wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides, proteins, and derivatives thereof. 123) The single-stranded oligonucleotide according to any one of 115) to 122), wherein the functional molecule is a lipid selected from the group consisting of cholesterol, fatty acids, fat-soluble vitamins, glycolipids, and glycerides. 124) The single-stranded oligonucleotide according to any one of 115) to 123), wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol, and tocotrienol. 125) The functional molecule is tocopherol, and the hydroxy group of the tocopherol is C 2-20 The single-stranded oligonucleotide according to any one of 115) to 117), which is bonded to the 5'-terminal or 3'-terminal nucleotide of the single-stranded oligonucleotide represented by formula (I) via an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group). 126) The hydroxy group of tocopherol is represented by the following formula (III): [ka] (In the formula, one * represents the bonding position (atom constituting the nucleotide) to the group derived from the oligonucleotide, and the other * represents the bonding position (atom constituting the group derived from the functional molecule) to the group derived from the functional molecule.) The single-stranded oligonucleotide according to any one of 115) to 117), wherein the single-stranded oligonucleotide is linked to the 5'-terminal or 3'-terminal nucleotide of the single-stranded oligonucleotide represented by formula (I) via a group represented by:

[0297] 127) The functional molecule is tocopherol, and the hydroxy group of the tocopherol is C 2-20The single-stranded oligonucleotide according to 115) or 118), wherein the single-stranded oligonucleotide is linked to a linking group comprising a non-nucleotide structure of the single-stranded oligonucleotide represented by formula (I) via an alkylene group (wherein the methylene groups of the alkylene group are each independently unsubstituted or substituted with -O-; the unsubstituted methylene groups are each independently unsubstituted or substituted with a hydroxy group or an oxo group). 128) The hydroxy group of tocopherol is C 2-20 The single-stranded oligonucleotide according to 115) or 118), wherein the single-stranded oligonucleotide is linked to a linking group containing a non-nucleotide structure of the single-stranded oligonucleotide represented by formula (I) via an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with an oxo group). 129) The single-stranded oligonucleotide according to 115), 118), 127), or 128), wherein the linking group containing a non-nucleotide structure has an -NH- group, and a group derived from the functional molecule is indirectly bonded to the nitrogen atom.

[0298] 130) The single-stranded oligonucleotide according to any one of 115) to 122), wherein the functional molecule is a sugar derivative that interacts with an asialoglycoprotein receptor. 131) The single-stranded oligonucleotide according to any one of 115) to 122), wherein the functional molecule is a peptide or protein selected from the group consisting of receptor ligands and antibodies.

[0299] B-1) The first oligonucleotide has the following formula: [ka] (In the formula, X 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide; X 2is a first nucleotide sequence portion, wherein the first nucleotide sequence is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide, and the oligonucleotide is covalently bonded to L. B-2) X 1 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from sugar-modified nucleotides, and X 2 is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, and X 3 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from sugar-modified nucleotides. B-3) X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, and X 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X 3 is a group derived from two or three oligonucleotides independently selected from sugar-modified nucleotides. B-4) X 1 is a group derived from an oligonucleotide consisting of 4 to 6 nucleotides independently selected from sugar-modified nucleotides, and X 2 is a group derived from an oligonucleotide consisting of 9 to 11 deoxyribonucleotides, and X 3 is a group derived from an oligonucleotide consisting of 4 to 6 nucleotides independently selected from sugar-modified nucleotides.

[0300] B-5) X1 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, and 2'-O-methylcarbamoylethylated nucleotides; and X 3 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-6) X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide and 2'-O-methylcarbamoylethylated nucleotide, and X 3 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-7) X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, and X 3 is a group derived from an oligonucleotide consisting of two or three LNAs. B-8) X 1 is a group derived from an oligonucleotide consisting of four to six 2'-O-methylcarbamoylethylated nucleotides, and X 3 is a group derived from an oligonucleotide consisting of 4 to 6 2'-O-methylcarbamoylethylated nucleotides.

[0301] B-9) The first oligonucleotide consists of 10 to 20 nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides; The single-stranded oligonucleotide according to any one of 1) to 24), wherein X is an antisense sequence portion, the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion are sugar-modified nucleotides, and the single-stranded oligonucleotide does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. B-10) A single-stranded oligonucleotide according to B-9), wherein the sugar-modified nucleotides contained in the first oligonucleotide are independently selected from LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides and 2'-O-methylcarbamoylethylated nucleotides. B-11) The single-stranded oligonucleotide according to B-10), wherein the sugar-modified nucleotides contained in the first oligonucleotide are independently selected from LNA and 2'-O-methylcarbamoylethylated nucleotides. B-12) A single-stranded oligonucleotide according to B-11), wherein the first oligonucleotide consists of 14 to 16 nucleotides independently selected from deoxyribonucleotides and LNAs.

[0302] B-13) At least one of the nucleotide sequence Xz and the nucleotide sequence Yz contains an antisense sequence, and the first oligonucleotide has the following formula: [ka] (In the formula, X 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide; X 2 is a first nucleotide sequence portion covalently linked to L). B-14) X1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, and X 2 is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides. B-15) X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-16) X 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0303] B-17) The second oligonucleotide has the following formula: [ka] (In the formula, Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 4 to 20 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and containing at least one ribonucleotide, and which is covalently bonded to L; Y 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and containing at least one sugar-modified nucleotide. B-18) Y 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, and Y1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. B-19) Y 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-20) Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0304] B-21) The second oligonucleotide has the following formula: [ka] (In the formula, Y 0 is a second nucleotide sequence portion covalently linked to L), a single-stranded oligonucleotide according to any one of 1) to 24) and B-1) to B-16).

[0305] B-22) The second oligonucleotide has the following formula: [ka] (In the formula, Y 0 is a second nucleotide sequence portion covalently linked to L and Ly. B-23) Y 0 is a group derived from an oligonucleotide consisting of 10 to 22 ribonucleotides.

[0306] B-24) The third oligonucleotide has the following formula: [ka] (In the formula, X Z 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide; X Z 2 is an antisense sequence portion contained in Xz, X Z 3 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide, and is covalently bonded to Lx). B-25) Xz 1 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from sugar-modified nucleotides, and Xz 2 is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, and Xz 3 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from sugar-modified nucleotides. B-26) X Z 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, and X Z 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X Z 3is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. B-27) Xz 1 is a group derived from an oligonucleotide consisting of 4 to 6 nucleotides independently selected from sugar-modified nucleotides, and Xz 2 is a group derived from an oligonucleotide consisting of 9 to 11 deoxyribonucleotides, and Xz 3 is a group derived from an oligonucleotide consisting of 4 to 6 nucleotides independently selected from sugar-modified nucleotides.

[0307] B-28) Xz 1 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide and 2'-O-methylcarbamoylethylated nucleotide, and Xz 3 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-29) X Z 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide and 2'-O-methylcarbamoylethylated nucleotide, and X Z 3is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-30) X Z 1 is a group derived from an oligonucleotide consisting of two or three LNAs, and X Z 3 is a group derived from an oligonucleotide consisting of two or three LNAs. B-31) Xz 1 is a group derived from an oligonucleotide consisting of four to six 2'-O-methylcarbamoylethylated nucleotides, and Xz 3 is a group derived from an oligonucleotide consisting of 4 to 6 2'-O-methylcarbamoylethylated nucleotides.

[0308] B-32) The third oligonucleotide consists of 10 to 20 nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides; A single-stranded oligonucleotide according to any one of B-1) to B-23), wherein Xz is an antisense sequence portion, the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion are sugar-modified nucleotides, and the single-stranded oligonucleotide does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. B-33) A single-stranded oligonucleotide according to B-32), wherein the sugar-modified nucleotides contained in the third oligonucleotide are independently selected from LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides and 2'-O-methylcarbamoylethylated nucleotides. B-34) The single-stranded oligonucleotide according to B-33), wherein the sugar-modified nucleotides contained in the third oligonucleotide are independently selected from LNA and 2'-O-methylcarbamoylethylated nucleotides. B-35) A single-stranded oligonucleotide according to B-34), wherein the third oligonucleotide consists of 14 to 16 nucleotides independently selected from deoxyribonucleotides and LNAs.

[0309] B-36) The third oligonucleotide has the following formula: [ka] (In the formula, Xz 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide; Xz 2 is a group derived from an oligonucleotide consisting of 4 to 20 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and containing at least one ribonucleotide, and is covalently bonded to Lx). B-37) Xz 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, and Xz 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides. B-38) Xz 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-39) Xz 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0310] B-40) The fourth oligonucleotide has the following formula: [ka] (In the formula, Y Z 3 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide, and is covalently linked to Ly; Y Z 2 is Y Z an antisense sequence portion comprising: Y Z 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide. B-41) Y Z 1 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from sugar-modified nucleotides, and Y Z 2 is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, and Y Z 3 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from sugar-modified nucleotides. B-42) Y Z 3is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, and Y Z 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and Y Z 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. B-43) Y Z 1 is a group derived from an oligonucleotide consisting of 4 to 6 nucleotides independently selected from sugar-modified nucleotides, and Y Z 2 is a group derived from an oligonucleotide consisting of 9 to 11 deoxyribonucleotides, and Y Z 3 is a group derived from an oligonucleotide consisting of 4 to 6 nucleotides independently selected from sugar-modified nucleotides.

[0311] B-44) Y Z 1 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, and 2'-O-methylcarbamoylethylated nucleotides; Y Z 3 is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-45) Y Z 1is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide and 2'-O-methylcarbamoylethylated nucleotide, and Y Z 3 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-46) Y Z 1 is a group derived from an oligonucleotide consisting of two or three LNAs, and Y Z 3 is a group derived from an oligonucleotide consisting of two or three LNAs. B-47) Y Z 1 is a group derived from an oligonucleotide consisting of four to six 2'-O-methylcarbamoylethylated nucleotides, and Y Z 3 is a group derived from an oligonucleotide consisting of 4 to 6 2'-O-methylcarbamoylethylated nucleotides.

[0312] B-48) The fourth oligonucleotide consists of 10 to 20 nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides; The single-stranded oligonucleotide according to any one of B-1) to B-39), wherein Yz is an antisense sequence portion, the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion are sugar-modified nucleotides, and the single-stranded oligonucleotide does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. B-49) A single-stranded oligonucleotide according to B-48), wherein the sugar-modified nucleotides contained in the fourth oligonucleotide are independently selected from LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides and 2'-O-methylcarbamoylethylated nucleotides. B-50) The single-stranded oligonucleotide according to B-49), wherein the sugar-modified nucleotides contained in the third oligonucleotide are independently selected from LNA and 2'-O-methylcarbamoylethylated nucleotides. B-51) A single-stranded oligonucleotide according to B-50), wherein the third oligonucleotide consists of 14 to 16 nucleotides independently selected from deoxyribonucleotides and LNAs.

[0313] B-52) The fourth oligonucleotide has the following formula: [ka] (Wherein, Yz 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 4 to 20 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and containing at least one ribonucleotide, and the oligonucleotide is covalently bonded to Ly; Yz 1 is a group derived from an oligonucleotide consisting of 1 to 10 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and containing at least one sugar-modified nucleotide. B-53) Yz 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, and Yz 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. B-54) Yz 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide, and 2'-O-methylcarbamoylethylated nucleotide. B-55) Yz 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0314] B-56) The group derived from the functional molecule is X 1 The single-stranded oligonucleotide according to any one of B-13) to B-16), wherein the nucleotide is directly or indirectly bound to the terminal nucleotide of the single-stranded oligonucleotide. B-57) The functional group is Y 1 The single-stranded oligonucleotide according to any one of B-17) to B-20), wherein the nucleotide is directly or indirectly bound to the terminal nucleotide of the single-stranded oligonucleotide. B-58) The functional group is Y 0 The single-stranded oligonucleotide according to any one of B-21) to B-23), wherein the nucleotide is directly or indirectly bound to the terminal nucleotide of the single-stranded oligonucleotide. B-59) The group derived from the functional molecule is Xz 1 The single-stranded oligonucleotide according to any one of B-36 to B-39), wherein the nucleotide is directly or indirectly linked to the terminal nucleotide of the single-stranded oligonucleotide. B-60) The group derived from the functional molecule is Yz 1 The single-stranded oligonucleotide according to any one of B-52 to B-55), wherein the nucleotide is directly or indirectly linked to the terminal nucleotide of the single-stranded oligonucleotide. B-61) A single-stranded oligonucleotide according to any one of B-1) to B-55), in which a group derived from a functional molecule is directly or indirectly bound to L.

[0315] C-1) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides}.

[0316] C-2) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}. C-3) B is C 2-20 The single-stranded oligonucleotide according to C-2), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and A is a group derived from tocopherol. C-4) B is Y 1 and the terminal nucleotide of the single-stranded oligonucleotide according to C-2) or C-3) above, linked via a phosphodiester bond.

[0317] C-5) X 1 , X 2 , X 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, 2 The single-stranded oligonucleotide according to any one of C-1) to C-4), wherein the nucleotides contained therein are linked to each other by phosphodiester bonds. C-6) X 1 and X 2 , X 2 and X 3 and Y 2 and Y 1 The single-stranded oligonucleotide according to any one of C-1) to C-5), wherein each terminal nucleotide is linked by a phosphorothioate bond.

[0318] C-7) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3is a group derived from an oligonucleotide consisting of two or three LNAs, X Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of 2'-O-methylated nucleotides and LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; L is represented by the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), Lx is represented by the following formula: [ka] (In the formula, W 6 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides}.

[0319] C-8) The following formula: [ka] (In the formula, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, X Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of 2'-O-methylated nucleotides and LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; L is represented by the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), Lx is represented by the following formula: [ka] (In the formula, W 6 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, a C alkyl group or a haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}. C-9) B is C 2-20 C-8) is a single-stranded oligonucleotide according to the present invention, wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-, and each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and A is a group derived from tocopherol. C-10) B is Y 1 and the terminal nucleotide of the single-stranded oligonucleotide according to C-8) or C-9) above, linked via a phosphodiester bond.

[0320] C-11) X 1 , X 2 , X 3 , X Z and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, 2 The single-stranded oligonucleotide according to any one of C-7) to C-10), wherein the nucleotides contained therein are linked to each other via phosphodiester bonds. C-12) X 1 and X 2 , X 2 and X 3 and Y 2 and Y 1The single-stranded oligonucleotide according to any one of C-7) to C-11), wherein each terminal nucleotide is linked by a phosphorothioate bond.

[0321] C-13) X Z However, the single-stranded oligonucleotide according to any one of C-7) to C-12) does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. C-14) X Z The single-stranded oligonucleotide according to C-13), wherein at least one of the nucleotides on the 3' and 5' sides is independently a nucleotide selected from 2'-O-methylated nucleotides and LNA. C-15) X Z The single-stranded oligonucleotide according to C-13) or C-14), wherein the nucleotides on the 3' and 5' ends of the single-stranded oligonucleotide are independently selected from 2'-O-methylated nucleotides and LNAs. C-16) X Z A single-stranded oligonucleotide according to any one of C-13) to C-15), wherein is a group derived from an oligonucleotide consisting of nucleotides independently selected from 2'-O-methylated nucleotides and LNA. C-17) Formula X Z - is a partial structure represented by formula X Z 1 -X Z 2 -X Z 3 - is represented by X Z 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X Z 2 is an antisense sequence portion contained in Xz, and is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, X Z 3 is a group derived from an oligonucleotide consisting of two or three LNAs.

[0322] C-18) L and Lx are each independently represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6). C-19) L is a compound of the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), Lx is represented by the following formula: [ka] (In the formula, W 6 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), or A single-stranded oligonucleotide according to any one of C-7) to C-17), which is -P(=O)(OH)-. C-20) A single-stranded oligonucleotide according to C-19), in which the nucleotides contained in Lx are linked to each other via phosphodiester bonds. C-21) L is the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), Lx is represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6). C-22) A single-stranded oligonucleotide according to C-21), in which the nucleotides contained in L are linked to each other via phosphodiester bonds.

[0323] C-23) X 1 and Y 1 and C-22) are hybridized intramolecularly. C-24) X 1 The base sequence of the nucleotides that make up Y 1 The single-stranded oligonucleotide according to any one of C-1) to C-23), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more. C-25) X 3 and Y 2 and C-24) are hybridized intramolecularly. C-26) Formula X 2 -X 3 The base sequence of the nucleotides constituting the partial structure represented by Y 2The single-stranded oligonucleotide according to any one of C-1) to C-25), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more.

[0324] C-27) Y 2 is a group derived from RNA consisting of 10 to 13 ribonucleotides.

[0325] C-28) The following formula: [ka] (In the formula, X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from 2'-O-methylated nucleotides and LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, L is represented by the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 0is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 15 ribonucleotides, Ly has the following formula: [ka] (In the formula, W 7 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), or -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y Z is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, which contains an antisense sequence portion and at least one of 2'-O-methylated nucleotides and LNA.

[0326] C-29) The following formula: [ka] wherein A is a group derived from a functional molecule, B is C 2-20 Alkylene group or C 2-20Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, a C alkyl group or a haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from 2'-O-methylated nucleotides and LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, L is represented by the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 0is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 15 ribonucleotides, Ly has the following formula: [ka] (In the formula, W 7 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y Z is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, which contains an antisense sequence portion and at least one of 2'-O-methylated nucleotides and LNA. C-30) B is C 2-20 C-29), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and A is a group derived from tocopherol. C-31) B is X 1 and the terminal nucleotide of the single-stranded oligonucleotide according to C-29) or C-30) above, linked via a phosphodiester bond.

[0327] C-32) X 1 , X 2 , Y Z The nucleotides contained in are linked to each other by phosphorothioate bonds, 0 The single-stranded oligonucleotide according to any one of C-28) to C-31), wherein the nucleotides contained therein are linked to each other by phosphodiester bonds. C-33) X 1 and X 2 The single-stranded oligonucleotide according to any one of C-28) to C-32), wherein each terminal nucleotide is linked by a phosphorothioate bond. C-34) X 2 and Y 0 and C-33) are hybridized intramolecularly. C-35) Formula X 1 -X 2 The base sequence of the nucleotides constituting the partial structure represented by Y 0 The single-stranded oligonucleotide according to any one of C-28) to C-34), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more. C-36) Y 0 is a group derived from RNA consisting of 10 to 15 ribonucleotides.

[0328] C-37) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, X 3is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, Ly has the following formula: [ka] (In the formula, W 7 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y Z is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, which contains an antisense sequence portion and at least one of 2'-O-methylated nucleotides and LNA.

[0329] C-38) The single-stranded oligonucleotide according to C-37), wherein the first nucleotide sequence is an antisense sequence.

[0330] C-39) X 1 , X 2 , X 3 and Y Z The nucleotides contained in are linked to each other by phosphorothioate bonds, 0 The single-stranded oligonucleotide according to C-37) or C-38), wherein the nucleotides contained in are linked to each other via phosphodiester bonds. C-40) X 1 and X 2 and X 2 and X 3 The single-stranded oligonucleotide according to any one of C-37) to C-39), wherein each terminal nucleotide is linked by a phosphorothioate bond. C-41) X 2 and Y 0 The single-stranded oligonucleotide according to any one of C-37) to C-40), wherein the following hybridizes intramolecularly: C-42) Formula X 1 -X 2 -X 3 The base sequence of the nucleotides constituting the partial structure represented by Y 0 The single-stranded oligonucleotide according to any one of C-37) to C-41), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more. C-43) Y 0is a group derived from RNA consisting of 12 to 16 ribonucleotides.

[0331] C-44) Formula-Y Z The partial structure represented by the formula -Y Z 3 -Y Z 2 -Y Z 1 is expressed as Y Z 1 is a group derived from an oligonucleotide consisting of two or three LNAs, Y Z 2 is an antisense sequence portion contained in Yz, and is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, Y Z 3 is a group derived from an oligonucleotide consisting of two or three LNAs. C-45) Y Z A single-stranded oligonucleotide according to any one of C-37) to C-43), which does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. C-46) Y Z The single-stranded oligonucleotide according to C-45), wherein at least one of the 3'- and 5'-nucleotides is independently a nucleotide selected from 2'-O-methylated nucleotides and LNA. C-47) Y Z The single-stranded oligonucleotide according to C-45) or C-46), wherein the nucleotides on the 3' and 5' ends of the single-stranded oligonucleotide are independently selected from 2'-O-methylated nucleotides and LNAs. C-48) Y Zis a group derived from an oligonucleotide consisting of nucleotides independently selected from 2'-O-methylated nucleotides and LNAs, a single-stranded oligonucleotide according to any one of C-45) to C-47).

[0332] C-49) L and Ly are each independently a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6). C-50) L is of the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), The single-stranded oligonucleotide according to any one of C-37) to C-48), wherein Ly is -P(=O)(OH)-. C-51) L is of the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), Ly is a compound of the formula: [ka] (In the formula, W 7 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides). C-52) A single-stranded oligonucleotide according to C-51), wherein the nucleotides contained in Ly are linked to each other via phosphodiester bonds. C-53) L is a compound of the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), Ly is a compound of the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6). C-54) A single-stranded oligonucleotide according to C-53), wherein the nucleotides contained in L are linked to each other via phosphodiester bonds.

[0333] C-55) The following formula: [ka] {In formula, Xz 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, Xz 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Lx is represented by the following formula: [ka] (In the formula, W 6 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, W 5is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, Ly has the following formula: [ka] (In the formula, W 7 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), or -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y Zis a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, which contains an antisense sequence portion and at least one of 2'-O-methylated nucleotides and LNA. C-56) The single-stranded oligonucleotide according to C-55), wherein the first nucleotide sequence is an antisense sequence.

[0334] C-57) The following formula: [ka] wherein A is a group derived from a functional molecule, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; Xz 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, Xz 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Lx is represented by the following formula: [ka] (In the formula, W 6is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), a group represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, Ly has the following formula: [ka] (In the formula, W 7 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), -P(=O)(OH)-, the formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer from 3 to 6) is a group represented by Y Z is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, which contains an antisense sequence portion and at least one of 2'-O-methylated nucleotides and LNA. C-58) The single-stranded oligonucleotide according to C-57), wherein the first nucleotide sequence is an antisense sequence. C-59) The single-stranded oligonucleotide according to C-57) or C-58), wherein B is a C2-20 alkylene group (each methylene group of the alkylene group is independently unsubstituted or replaced by -O-; each unsubstituted methylene group is independently unsubstituted or substituted by a hydroxy group), and A is a group derived from tocopherol. C-60) B is Xz 1 and the terminal nucleotide of the single-stranded oligonucleotide according to any one of C57) to C-59) linked by a phosphodiester bond.

[0335] C-61) Xz 1 , X 1 , X 2 , X 3 and Y Z The nucleotides contained in Xz are linked to each other by phosphorothioate bonds. 2 and Y 0 The single-stranded oligonucleotide according to any one of C-55) to C-60), wherein the nucleotides contained therein are linked to each other by phosphodiester bonds. C-62) Xz 1 and Xz 2 , X 1 and X 2 , X 2 and X 3 The terminal nucleotides of each of the Xz 2 and X 1 , and Y 0 and Y Z The single-stranded oligonucleotide according to any one of C-55) to C-61), wherein the terminal nucleotides of each of the following are linked by a phosphodiester bond: C-63) X 2 and Y 0 and C-62) are hybridized intramolecularly. C-64) Formula X 1 -X 2 -X 3The base sequence of the nucleotides constituting the partial structure represented by Y 0 The single-stranded oligonucleotide according to any one of C-55) to C-63), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-65) Xz 2 and Y Z and C-64) are hybridized intramolecularly. C-66) Xz 2 The base sequence of the nucleotides that make up Y Z The single-stranded oligonucleotide according to any one of C-55) to C-65), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-67) Xz 1 and Y Z The single-stranded oligonucleotide according to any one of C-55) to C-66), wherein the following hybridizes intramolecularly: C-68) Xz 1 The base sequence of the nucleotides that make up Y Z The single-stranded oligonucleotide according to any one of C-55) to C-67), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more.

[0336] C-69) Formula-Y Z The partial structure represented by the formula -Yz 3 -Yz 2 -Yz 1 is expressed as Yz 1 is a group derived from an oligonucleotide consisting of two or three LNAs, Yz 2 is an antisense sequence portion contained in Yz, and is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, Y Z 3 is a group derived from an oligonucleotide consisting of two or three LNAs.

[0337] C-70) Xz 2 and formula Yz 2 -Yz 3 The single-stranded oligonucleotide according to C-69) hybridizes intramolecularly with a partial structure represented by the following formula: C-71) Xz 2 and the base sequence of nucleotides that make up the formula Yz 2 -Yz 3 The single-stranded oligonucleotide according to C-69) or C-70), wherein the complementarity with the base sequence of the nucleotide constituting the partial structure represented by C-72) Xz 1 and Yz 1 and C-71) are hybridized intramolecularly. C-73) Xz 1 The base sequence of the nucleotides that make up Yz 1 The single-stranded oligonucleotide according to any one of C-69) to C-72), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more.

[0338] C-74) A single-stranded oligonucleotide according to any one of C-55) to C-68), wherein Yz does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. C-75) The single-stranded oligonucleotide according to C-74), wherein at least one of the nucleotides on the 3' and 5' sides of Yz is independently a nucleotide selected from 2'-O-methylated nucleotides and LNA. C-76) A single-stranded oligonucleotide according to C-74) or C-75), wherein the nucleotides on the 3' and 5' sides of Yz are independently selected from 2'-O-methylated nucleotides and LNA. C-77) A single-stranded oligonucleotide according to any one of C-74) to C-76), wherein Yz is a group derived from an oligonucleotide consisting of nucleotides independently selected from 2'-O-methylated nucleotides and LNA.

[0339] C-78) L, Lx, and Ly each independently represent the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6). C-79) L is of the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), The single-stranded oligonucleotide according to any one of C-55) to C-77), wherein Lx and Ly are -P(=O)(OH)-. C-80) L is of the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6), Lx is represented by the following formula: [ka] (In the formula, W 6 is a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), Ly is a compound of the formula: [ka] (In the formula, W 7 are each independently a group derived from an oligonucleotide consisting of 1 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides). C-81) A single-stranded oligonucleotide according to C-80), wherein the nucleotides contained in Lx and Ly are linked to each other via a phosphodiester bond. C-82) L is of the following formula: [ka] (In the formula, W 5 is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides), Lx and Ly each independently represent the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (wherein s is an integer of 3 to 6). C-83) A single-stranded oligonucleotide according to C-82), wherein the nucleotides contained in L are linked to each other via phosphodiester bonds.

[0340] C-84) Xz 2 is a group derived from RNA consisting of 10 to 13 ribonucleotides. C-85) Y 0 is a group derived from RNA consisting of 12 to 16 ribonucleotides.

[0341] C-86) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, P 2 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 1 is an integer between 1 and 10, and s 22 is an integer between 0 and 4) is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides}. C-87) P 2 is —P(═O)(OH)—.

[0342] C-88) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] {where, V 2 is represented by the following formula (XII-1), (XII-3), (XII-7) or (XII-8): [ka] (In the formula, о 2 is an integer from 1 to 6, and p 2 is an integer from 1 to 6, and d 2 is an integer of 1 to 6)}; Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides}.

[0343] C-89) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, P 4 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 44 is an integer between 0 and 9, and V 4 is represented by the following formula (XII-10): [ka] is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides}. C-90) P 4 is —P(═O)(OH)—.

[0344] C-91) The formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] {where, V 14 are each independently represented by the following formula (XIV-10) or (XIV-11): [ka] (Wherein, w is 0 or 1, Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C1-6 Alkylaminosulfonyl group or diC 1-6 an alkylaminosulfonyl group, a ribonucleoside group, or a deoxyribonucleoside group), At least one V 14 is a group represented by the formula (XIV-10) or (XIV-11), P 14 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 14 is -P(=O)(OH)-, s 14 is an integer between 0 and 9, and s 14 When is 1 or more, V 14 are groups represented by the following formula: Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides}. C-92) P 14 is —P(═O)(OH)—.

[0345] C-93) The formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, P 2 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 1 is an integer between 1 and 10, and s 22 is an integer between 0 and 4) is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}. C-94) P 2 is —P(═O)(OH)—. The single-stranded oligonucleotide according to C-93).

[0346] C-95) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] {where, V 2 is represented by the following formula (XII-1), (XII-3), (XII-7) or (XII-8): [ka] (In the formula, о 2 is an integer from 1 to 6, and p 2 is an integer from 1 to 6, and d 2 is an integer of 1 to 6)}; Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}.

[0347] C-96) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (In the formula, P 4 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 44 is an integer between 0 and 9, and V 4 is represented by the following formula (XII-10): [ka] is a group represented by Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}. C-97) P 4 is —P(═O)(OH)—.

[0348] C-98) The formula: TIFF0007601080000201.tif10161 {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] {where, V 14 are each independently represented by the following formula (XIV-10) or (XIV-11): [ka] (Wherein, w is 0 or 1, Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C 1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 an alkylaminosulfonyl group, a ribonucleoside group, or a deoxyribonucleoside group), At least one V 14 is a group represented by the formula (XIV-10) or (XIV-11), P 14 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 14 is -P(=O)(OH)-, s 14 is an integer between 0 and 9, and s 14 When is 1 or more, V 14 are groups represented by the following formula: Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}. C-99) P 14 is —P(═O)(OH)—.

[0349] C-100) B is C 2-20 A single-stranded oligonucleotide according to any one of C-93) to C-99), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or replaced by -O-, and each unsubstituted methylene group is independently unsubstituted or substituted by a hydroxy group), and A is a group derived from tocopherol. C-101) B is Y1 and the terminal nucleotide of the single-stranded oligonucleotide according to any one of C-93) to C-100) linked by a phosphodiester bond.

[0350] C-102) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] {where, V 12 teeth, C 2-20 Alkylene group (the C 2-20 The alkylene group is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy groups and amino groups; The following formula (VIII-2, 3, 9 or 11): [ka] (In the formula, о 1 is an integer between 0 and 10, and p 1 is an integer between 0 and 10, and d 1 is an integer between 1 and 10) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 12 is C 2-20Alkylene group (the C 2-20 the alkylene group is substituted with one or more substituents selected from the group consisting of a hydroxy group and an amino group), or a group selected from the formula (VIII-2, 3, 9 or 11), P 12 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 12 is -P(=O)(OH)-, q7 is an integer of 1 to 10, q8 is an integer of 1 to 6, and when at least one of q7 and q8 is 2 or more, V 12 are groups represented by the following formula: Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}.

[0351] C-103) B is C 2-20The single-stranded oligonucleotide according to C-102), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group, an amino group, or an oxo group), and A is a group derived from tocopherol. C-104) The single-stranded oligonucleotide according to C-102) or C-103), wherein B is linked to the moiety obtained by removing a hydrogen atom from the amino group of L.

[0352] C-105) P 12 The single-stranded oligonucleotide according to any one of C-102) to C-104), wherein is —P(═O)(OH)—.

[0353] C-106) X 1 , X 2 , X 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, 2 The single-stranded oligonucleotide according to any one of C-86) to C-105), wherein the nucleotides contained therein are linked to each other by phosphodiester bonds. C-107) X 1 and X 2 , X 2 and X 3 and Y 2 and Y 1 The single-stranded oligonucleotide according to any one of C-86) to C-102), wherein each terminal nucleotide is linked by a phosphorothioate bond.

[0354] C-108) X 1 and Y 1 The single-stranded oligonucleotide according to any one of C-86) to C-107), wherein the following hybridizes intramolecularly: C-109) X 1 The base sequence of the nucleotides that make up Y 1The single-stranded oligonucleotide according to any one of C-86) to C-108), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more. C-110) X 3 and Y 2 The single-stranded oligonucleotide according to any one of C-86) to C-109), wherein the following hybridizes intramolecularly: C-111) Formula X 2 -X 3 The base sequence of the nucleotides constituting the partial structure represented by Y 2 The single-stranded oligonucleotide according to any one of C-86) to C-110), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more.

[0355] C-112) Y 2 is a group derived from RNA consisting of 10 to 13 ribonucleotides.

[0356] C-113) The following formula: [ka] {where, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and has a first nucleotide sequence that is an antisense sequence, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs, L is represented by the following formula: [ka] (wherein r is an integer from 10 to 15) or a group represented by the following formula: [ka] (In the formula, P 2 are each independently -P(=O)(OH)- or -P(=O)(SH)-, and s 1 is an integer between 1 and 10, and s 22 is an integer between 0 and 4) or a group represented by the following formula: [ka] {where, V 2 is represented by the following formula (XII-1), (XII-3), (XII-7) or (XII-8): [ka] (In the formula, о 2 is an integer from 1 to 6, and p 2 is an integer from 1 to 6, and d 2 is an integer of 1 to 6)}, or a group represented by the following formula: [ka] {where, V 14 are each independently represented by the following formula (XIV-10) or (XIV-11): [ka] (Wherein, w is 0 or 1, Rc is a hydrogen atom, C 1-6 Alkyl group, halo C 1-6 Alkyl group, C 1-6 Alkylcarbonyl group, haloC 1-6 Alkylcarbonyl group, C 1-6 Alkoxycarbonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxycarbonyl group, mono C 1-6 Alkylaminocarbonyl group, diC 1-6 Alkylaminocarbonyl group, C1-6 Alkylsulfonyl group, haloC 1-6 Alkylsulfonyl group, C 1-6 Alkoxysulfonyl group, C 1-6 C substituted with an alkoxy group or a carbamoyl group 1-6 Alkoxysulfonyl group, mono C 1-6 Alkylaminosulfonyl group or diC 1-6 an alkylaminosulfonyl group, a ribonucleoside group, or a deoxyribonucleoside group), At least one V 14 is a group represented by the formula (XIV-10) or (XIV-11), P 14 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 14 is -P(=O)(OH)-, s 14 is an integer between 0 and 9, and s 14 When is 1 or more, V 14 are groups represented by the following formula: Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}.

[0357] C-114) B is C 2-20 C-113), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-, and each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and A is a group derived from tocopherol. C-115) B is Y 0 and the terminal nucleotide of the single-stranded oligonucleotide according to C-113) or C-114) linked via a phosphodiester bond.

[0358] C-116) P 2 and P 14 The single-stranded oligonucleotide according to any one of C-113) to C-115), wherein is —P(═O)(OH)—. C-117) X 1 , X 2 and X 3 The nucleotides contained in are linked to each other by phosphorothioate bonds, 0 The single-stranded oligonucleotide according to C-113) to C-116), wherein the nucleotides contained therein are linked to each other by phosphodiester bonds. C-118) X 1 and X 2 , and X 2 and X 3 The single-stranded oligonucleotide according to any one of C-113) to C-117), wherein each terminal nucleotide is linked by a phosphorothioate bond.

[0359] C-119) X 2 and Y 0 The single-stranded oligonucleotide according to any one of C-113) to C-118), wherein the following hybridize intramolecularly: C-120) X2 The base sequence of the nucleotides that make up Y 0 The single-stranded oligonucleotide according to any one of C-113) to C-119), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-121) X 1 and X 3 But, Y 0 A single-stranded oligonucleotide according to any one of C-113) to C-120), which hybridizes intramolecularly with C-122) Formula X 1 -X 2 -X 3 The base sequence of the nucleotides constituting the partial structure represented by Y 0 The single-stranded oligonucleotide according to any one of C-113) to C-121), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more.

[0360] C-123) The following formula: [ka] {wherein X has at least one selected from 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and contains an antisense sequence portion and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides; L is the same as defined in C-113) above, Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 15 ribonucleotides, Y 1is a group derived from an oligonucleotide consisting of 2 to 5 2'-O-methylated nucleotides}.

[0361] C-124) The following formula: [ka] {wherein X has at least one selected from 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and contains an antisense sequence portion and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides; L is the same as defined in C-113) above, Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 15 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of 2 to 5 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}.

[0362] C-125) B is C 2-20 C-124), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and A is a group derived from tocopherol. C-126) B is Y 1 and the terminal nucleotide of the single-stranded oligonucleotide according to C-124) or C-125) linked by a phosphodiester bond.

[0363] C-127) P 2 and P 14 The single-stranded oligonucleotide according to any one of C-123) to C-126), wherein is —P(═O)(OH)—.

[0364] C-128) The following formula: [ka] {wherein X has at least one selected from 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and contains an antisense sequence portion and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides; L is represented by the following formula: [ka] {where, V 12 teeth, C 2-20 Alkylene group (the C 2-20 The alkylene group is unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy groups and amino groups; The following formula (VIII-2, 3, 9 or 11): [ka] (In the formula, о 1 is an integer between 0 and 10, and p 1 is an integer between 0 and 10, and d 1 is an integer between 1 and 10) a group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V 12 is C 2-20 Alkylene group (the C 2-20 the alkylene group is substituted with one or more substituents selected from the group consisting of a hydroxy group and an amino group), or a group selected from the formula (VIII-2, 3, 9 or 11), P 12 are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P 12 is -P(=O)(OH)-, q7 is an integer of 1 to 10, q8 is an integer of 1 to 6, and when at least one of q7 and q8 is 2 or more, V 12 are groups represented by the following formula: Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 15 ribonucleotides, Y 1is a group derived from an oligonucleotide consisting of 2 to 5 2'-O-methylated nucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}.

[0365] C-129) B is C 2-20 C-128), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group, an amino group, or an oxo group), and A is a group derived from tocopherol. C-130) The single-stranded oligonucleotide according to C-128) or C-129), wherein B is linked to the moiety obtained by removing a hydrogen atom from the amino group of L.

[0366] C-131) P 12 The single-stranded oligonucleotide according to any one of C-128) to C-130), wherein is —P(═O)(OH)—. C-132) X and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, 2The single-stranded oligonucleotides described in C-123) to C-131) are represented by the formula: wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-133) Y 2 and Y 1 The single-stranded oligonucleotide according to any one of C-123) to C-132), wherein the terminal nucleotide is linked via a phosphorothioate bond.

[0367] C-134) X and Y 2 The single-stranded oligonucleotide according to any one of C-123) to C-133), wherein the following hybridizes intramolecularly: C-135) What is the base sequence of nucleotides that make up X and Y? 2 The single-stranded oligonucleotide according to any one of C-123) to C-134), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-136) X and Y 1 The single-stranded oligonucleotide according to any one of C-123) to C-135), wherein the following hybridize intramolecularly: C-137) What is the base sequence of nucleotides that make up X and the formula Y? 2 -Y 1 The single-stranded oligonucleotide according to any one of C-123) to C-136), wherein the complementarity with the base sequence of the nucleotide constituting the partial structure represented by

[0368] C-138) The following formula: [ka] {wherein X has at least one selected from 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and is a group derived from an oligonucleotide consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-methylcarbamoylethylated nucleotides, and LNA, and contains an antisense sequence portion and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides; L is the same as defined in C-113) above, Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 20 ribonucleotides, B is C 2-20 Alkylene group or C 2-20 Alkenylene group (the methylene groups contained in the alkylene group and alkenylene group are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxy group, a protected hydroxy group, an oxo group, and a thioxo group. The methylene groups of the alkylene group and alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R B is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl group), -S-, -S(=O)- or -S(=O)2-; A is a group derived from a functional molecule}.

[0369] C-139) B is C 2-20C-138), wherein A is an alkylene group (each methylene group of the alkylene group is independently unsubstituted or substituted with -O-; each unsubstituted methylene group is independently unsubstituted or substituted with a hydroxy group), and A is a group derived from tocopherol. C-140) B is Y 0 and the terminal nucleotide of the single-stranded oligonucleotide according to C-138) or C-139) linked via a phosphodiester bond.

[0370] C-141) P 2 and P 14 The single-stranded oligonucleotide according to any one of C-138) to C-140), wherein is —P(═O)(OH)—. C-142) The nucleotides in X are linked to each other by phosphorothioate bonds, and Y 0 The single-stranded oligonucleotide according to C-138) to C-141), wherein the nucleotides contained therein are linked to each other by phosphodiester bonds.

[0371] C-143) X and Y 0 The single-stranded oligonucleotide according to any one of C-138) to C-142), wherein the following hybridizes intramolecularly: C-144) What is the base sequence of nucleotides that make up X and Y? 0 The single-stranded oligonucleotide according to any one of C-138) to C-143), wherein the complementarity with the base sequence of the nucleotides constituting the single-stranded oligonucleotide is 70% or more.

[0372] C-145) The following formula: [ka] {where, X 1is a group derived from an oligonucleotide consisting of 2 to 6 nucleotides independently selected fro...

Claims

1. The following formula (I): 【Chemistry 1】 X is consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; a group derived from a first oligonucleotide comprising at least one sugar-modified nucleotide, Y is, a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and including at least one ribonucleotide; Xz is a group derived from a third oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; Yz is, a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; L is, a linking group comprising a non-nucleotide structure, Lx is -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the following formula: 【Chemistry 3】 (In the formula, P ６ are each independently -P(=O)(OH)- or -P(=O)(SH)-, W ６ is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; Ly is, -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the following formula: 【Chemistry 4】 (In the formula, P ７ are each independently -P(=O)(OH)- or -P(=O)(SH)-, W ７ is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; The linking groups each independently represent the following formula: 【Chemistry 5】 [In the formula, V １１ teeth, C ２－５０ Alkylene group (C ２－５０ The alkylene group is unsubstituted or is selected from the group consisting of the substituents V ａ substituted with one or more independently selected substituents from The following formulas (XIII-1) to (XIII-11): 【Chemistry 6】 (In the formula, о １ is an integer from 0 to 30; p １ is an integer from 0 to 30; d １ is an integer from 1 to 10, w is an integer from 0 to 3, Rb is a halogen atom, a hydroxyl group, an amino group, C １－６ Alkoxy group, C １－６ C substituted with an alkoxy group or a carbamoyl group １－６ Alkoxy group, mono C １－６ Alkylamino group, diC １－６ Alkylamino group or C １－６ Rc is a hydrogen atom, C １－６ Alkyl group, haloC １－６ Alkyl group, C １－６ Alkylcarbonyl group, haloC １－６ Alkylcarbonyl group, C １－６ Alkoxycarbonyl group, C １－６ C substituted with an alkoxy group or a carbamoyl group １－６ Alkoxycarbonyl group, mono C １－６ Alkylaminocarbonyl group, diC １－６ Alkylaminocarbonyl group, C １－６ Alkylsulfonyl group, haloC １－６ Alkylsulfonyl group, C １－６ Alkoxysulfonyl group, C １－６ C substituted with an alkoxy group or a carbamoyl group １－６ Alkoxysulfonyl group, mono C １－６ Alkylaminosulfonyl group or diC １－６ alkylaminosulfonyl group) A group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V １１ is C ２－５０ Alkylene group (C ２－５０ The alkylene group is unsubstituted or is selected from the group consisting of the substituents V ａ substituted with one or more substituents independently selected from the following: or a group selected from formulas (XIII-1) to (XIII-11): Substituent group V ａ means a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, P １１ are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P １１ is -P(=O)(OH)-, q １１ is an integer from 1 to 10, and q １２ is an integer from 1 to 20, and q １１ and q １２ When at least one of is 2 or more, V １１ are the same or different, L is covalently linked at both ends to the first oligonucleotide and the second oligonucleotide, Lx is covalently bound to the first oligonucleotide and the third oligonucleotide at both ends thereof, Ly is covalently linked at both ends to the second oligonucleotide and the fourth oligonucleotide, m is 0 or 1, n is 0, said first oligonucleotide having a nucleotide sequence X, said second oligonucleotide having a nucleotide sequence Y, said third oligonucleotide having a nucleotide sequence Xz, and said fourth oligonucleotide having a nucleotide sequence Yz; said nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing to at least a portion of a second oligonucleotide; the nucleotide sequence Y is capable of hybridizing to at least a portion of the first oligonucleotide, comprises a second nucleotide sequence consisting of 4 to 25 ribonucleotides, and has 1 to 10 sugar-modified nucleotides bound adjacent to at least one of the 5' and 3' ends of the second nucleotide sequence portion; the nucleotide sequence X comprises an antisense sequence capable of hybridizing to a target RNA, the first nucleotide sequence portion is composed of nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides, comprises at least one sugar-modified nucleotide, does not comprise an oligonucleotide chain composed of four consecutive deoxyribonucleotides, and at least one nucleotide is phosphorothioated; When the nucleic acid has two or more antisense sequences, the target RNAs to which the respective antisense sequence portions hybridize may be the same or different. The sugar-modified nucleotide in X is at least one selected from the group consisting of hexitol nucleotides, cyclohexene nucleotides, peptide nucleic acids, glycol nucleic acids, threo nucleotides, morpholino nucleic acids, tricyclo-DNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-aminopropylated nucleotides, 2'-fluorinated nucleotides, 2'-F-arabinonucleotides, bridged nucleotides, and 2'-O-methylcarbamoylethylated nucleotides. wherein X and Y hybridize at a first nucleotide sequence portion and a second nucleotide sequence portion.

2. The following formula (I): 【Chemistry 7】 wherein X is consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; a group derived from a first oligonucleotide comprising at least one sugar-modified nucleotide, Y is, a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and including at least one ribonucleotide; Xz is, a group derived from a third oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; Yz is, a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; L is, a linking group comprising a non-nucleotide structure, Lx is -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the following formula: 【Chemistry 9】 (In the formula, W ６ is a group derived from a sixth oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; Ly is, -P(=O)(OH)-, a linking group containing a non-nucleotide structure, or the following formula: 【Chemistry 10】 (In the formula, W ７ is a group derived from a seventh oligonucleotide consisting of 1 to 50 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides; The linking groups each independently represent the following formula: 【Chemistry 11】 [In the formula, V １１ teeth, C ２－５０ Alkylene group (C ２－５０ The alkylene group is unsubstituted or is selected from the group consisting of the substituents V ａ substituted with one or more independently selected substituents from The following formulas (XIII-1) to (XIII-11): 【Chemistry 12】 (In the formula, о １ is an integer from 0 to 30; p １ is an integer from 0 to 30; d １ is an integer from 1 to 10, w is an integer from 0 to 3, Rb is a halogen atom, a hydroxyl group, an amino group, C １－６ Alkoxy group, C １－６ C substituted with an alkoxy group or a carbamoyl group １－６ Alkoxy group, mono C １－６ Alkylamino group, diC １－６ Alkylamino group or C １－６ Rc is a hydrogen atom, C １－６ Alkyl group, haloC １－６ Alkyl group, C １－６ Alkylcarbonyl group, haloC １－６ Alkylcarbonyl group, C １－６ Alkoxycarbonyl group, C １－６ C substituted with an alkoxy group or a carbamoyl group １－６ Alkoxycarbonyl group, mono C １－６ Alkylaminocarbonyl group, diC １－６ Alkylaminocarbonyl group, C １－６ Alkylsulfonyl group, haloC １－６ Alkylsulfonyl group, C １－６ Alkoxysulfonyl group, C １－６ C substituted with an alkoxy group or a carbamoyl group １－６ Alkoxysulfonyl group, mono C １－６ Alkylaminosulfonyl group or diC １－６ alkylaminosulfonyl group) A group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V １１ is C ２－５０ Alkylene group (C ２－５０ The alkylene group is unsubstituted or is selected from the group consisting of the substituents V ａ substituted with one or more substituents independently selected from the following: or a group selected from formulas (XIII-1) to (XIII-11): Substituent group V ａ means a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, P １１ are each independently -P(=O)(OH)- or -P(=O)(SH)-; At least one P １１ is -P(=O)(OH)-, q １１ is an integer from 1 to 10, and q １２ is an integer from 1 to 20, and q １１ and q １２ When at least one of is 2 or more, V １１ are the same or different, L is covalently linked at both ends to the first oligonucleotide and the second oligonucleotide, Lx is covalently bound to the first oligonucleotide and the third oligonucleotide at both ends thereof, Ly is covalently linked at both ends to the second oligonucleotide and the fourth oligonucleotide, m is 0 or 1, n is 0, said first oligonucleotide having a nucleotide sequence X, said second oligonucleotide having a nucleotide sequence Y, said third oligonucleotide having a nucleotide sequence Xz, and said fourth oligonucleotide having a nucleotide sequence Yz; said nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing to at least a portion of a second oligonucleotide; the nucleotide sequence Y is capable of hybridizing to at least a portion of the first oligonucleotide, comprises a second nucleotide sequence consisting of 4 to 25 ribonucleotides, and has 1 to 10 sugar-modified nucleotides bound adjacent to at least one of the 5' and 3' ends of the second nucleotide sequence portion; the nucleotide sequence X comprises an antisense sequence capable of hybridizing to a target RNA, the first nucleotide sequence portion is composed of nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides, comprises at least one sugar-modified nucleotide, does not comprise an oligonucleotide chain composed of four consecutive deoxyribonucleotides, and at least one nucleotide is phosphorothioated; When the nucleic acid has two or more antisense sequences, the target RNAs to which the respective antisense sequence portions hybridize may be the same or different. The sugar-modified nucleotide in X is at least one selected from the group consisting of hexitol nucleotides, cyclohexene nucleotides, peptide nucleic acids, glycol nucleic acids, threo nucleotides, morpholino nucleic acids, tricyclo-DNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-aminopropylated nucleotides, 2'-fluorinated nucleotides, 2'-F-arabinonucleotides, bridged nucleotides, and 2'-O-methylcarbamoylethylated nucleotides. wherein X and Y hybridize at a first nucleotide sequence portion and a second nucleotide sequence portion.

3. 3. The single-stranded oligonucleotide according to claim 1, wherein X is bound to L at the 3' side and Y is bound to L at the 5' side.

4. 3. The single-stranded oligonucleotide according to claim 1, wherein X is bound to L at the 5' side and Y is bound to L at the 3' side.

5. The linking groups containing a non-nucleotide structure each independently have the following formula: 【Chemistry 13】 {In the formula, V ０ teeth, C ２－５０ Alkylene group (C ２－５０ The alkylene group is unsubstituted or is selected from the group consisting of the substituents V ａ substituted with one or more independently selected substituents from The following formulas (X-1) to (X-9): 【Chemistry 14】 (In the formula, o is an integer from 0 to 30, and p is an integer from 0 to 30.) A group selected from the group consisting of a ribonucleoside group, or is a deoxyribonucleoside group, At least one V ０ is C ２－５０ Alkylene group (C ２－５０ The alkylene group is unsubstituted or is selected from the group consisting of the substituents V ａ substituted with one or more substituents independently selected from A group selected from the formulas (X-1) to (X-9), Substituent group V ａ means a group of substituents consisting of a hydroxy group, a halogen atom, a cyano group, a nitro group, an amino group, a carboxy group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, and a formyl group, q １ is an integer from 1 to 10, and q ２ is an integer from 1 to 20, and q １ and q ２ When at least one of is 2 or more, V ０ The single-stranded oligonucleotide according to any one of claims 1 to 4, wherein the aryl group is a group represented by the formula (I) and (II) above.

6. 6. The single-stranded oligonucleotide of claim 1, wherein the first nucleotide sequence is an antisense sequence.

7. 7. A single-stranded oligonucleotide according to any one of claims 1 to 6, wherein the first oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the first nucleotide sequence portion.

8. 8. The single-stranded oligonucleotide according to any one of claims 1 to 7, wherein the first nucleotide sequence is a sequence of 4 to 20 nucleotides including at least one deoxyribonucleotide.

9. 9. The single-stranded oligonucleotide of claim 1, wherein the second nucleotide sequence is a sequence comprising at least four consecutive nucleotides that are cleaved by RNase H.

10. 10. The single-stranded oligonucleotide according to claim 1, wherein the second oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the second nucleotide sequence portion.

11. 11. The single-stranded oligonucleotide of claim 1, wherein m is 0, n is 0, and L is a linking group comprising a non-nucleotide structure.

12. 11. The single-stranded oligonucleotide of claim 1, wherein m is 1 and Xz comprises at least one ribonucleotide.

13. 11. The single-stranded oligonucleotide according to any one of claims 1 to 10, wherein m is 1 and Xz comprises at least 4 consecutive nucleotides that are cleaved by RNase H.

14. 11. The single-stranded oligonucleotide of claim 1, wherein m is 1, Xz comprises at least one sugar-modified nucleotide, and the nucleotide sequence Xz comprises an antisense sequence.

15. The single-stranded oligonucleotide according to any one of claims 1 to 14, wherein the sugar-modified nucleotide is at least one selected from the group consisting of hexitol nucleotides, cyclohexene nucleotides, peptide nucleic acids, glycol nucleic acids, threo nucleotides, morpholino nucleic acids, tricyclo-DNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides, 2'-O-aminopropylated nucleotides, 2'-fluorinated nucleotides, 2'-F-arabinonucleotides, bridged nucleotides, and 2'-O-methylcarbamoylethylated nucleotides.

16. A single-stranded oligonucleotide according to any one of claims 1 to 15, wherein the second nucleotide sequence consists of 6 to 20 ribonucleotides.

17. A single-stranded oligonucleotide according to any one of claims 1 to 15, wherein the second nucleotide sequence consists of 8 to 15 ribonucleotides.

18. The second oligonucleotide is represented by the formula Y 2 -Y 1 or the formula Y 0 , wherein Y 2 is a second nucleotide sequence moiety, which is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, and which is covalently linked to L; Y 1 is a group derived from an oligonucleotide consisting of 2 or 3 nucleotides independently selected from sugar-modified nucleotides; The single-stranded oligonucleotide according to any one of claims 1 to 15, wherein Y 0 is a second nucleotide sequence moiety, covalently linked to L, and is a group derived from an oligonucleotide consisting of 10 to 22 ribonucleotides.

19. A single-stranded oligonucleotide described in any one of claims 1 to 18, further comprising a group derived from a functional molecule having at least one function selected from the group consisting of a labeling function, a purification function, and a delivery function to a target site.

20. 20. The single-stranded oligonucleotide of claim 19, wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides and proteins, and derivatives thereof.

21. 21. The single-stranded oligonucleotide of claim 19 or 20, wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol and tocotrienol.

22. 21. The single-stranded oligonucleotide of claim 19 or 20, wherein the functional molecule is a sugar derivative that interacts with an asialoglycoprotein receptor.

23. 21. The single-stranded oligonucleotide of claim 19 or 20, wherein the functional molecule is a peptide or protein selected from the group consisting of a receptor ligand and an antibody.

24. 24. A pharmaceutical composition comprising the single-stranded oligonucleotide of any one of claims 1 to 23 and a pharmacologically acceptable carrier.

25. A method for regulating the function of a target RNA, comprising the step of contacting a single-stranded oligonucleotide according to any one of claims 1 to 23 with a cell (excluding a human cell).

26. A method for regulating the function of a target RNA in a mammal (excluding humans), comprising the step of administering to the mammal a pharmaceutical composition comprising a single-stranded oligonucleotide described in any one of claims 1 to 23.

27. 24. A method for controlling expression of a target gene, comprising the step of contacting a cell (excluding a human cell) with a single-stranded oligonucleotide according to any one of claims 1 to 23.

28. A method for controlling expression of a target gene in a mammal (excluding humans), comprising the step of administering to the mammal a pharmaceutical composition comprising a single-stranded oligonucleotide described in any one of claims 1 to 23.

29. 24. A method for producing a single-stranded oligonucleotide according to any one of claims 1 to 23, comprising extending a nucleotide chain at the 3'-end or 5'-end of an oligonucleotide comprising at least one of X, L and Y.

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