Single-stranded oligonucleotide

Abstract

To provide a single-stranded oligonucleotide capable of controlling a gene of interest at high efficiency and being produced easily.SOLUTION: Provided is a single-stranded oligonucleotide represented by the formula X-L-Y in which X and Y hybridize with a first nucleotide sequence portion and a second nucleotide sequence portion. X comprises 7-100 nucleotides, includes at least one modified nucleotide, can hybridize with a second oligonucleotide, and has a first nucleotide sequence including at least four consecutive nucleotides recognized by RNase H. Y comprises 4-100 nucleotides, can hybridize with the first oligonucleotide, and has a second nucleotide sequence including at least one ribonucleotide. At least one of nucleotide sequence X and Y has an antisense sequence that can hybridize with an RNA of interest. L is a group derived from a third oligonucleotide that is degraded under physiological conditions.SELECTED DRAWING: None

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 ribosomal RNA, transfer RNA, miRNA, or other ncRNA (non-coding RNA) of a target gene, and are single-stranded DNA, RNA, and / or structural analogs thereof consisting of about 8 to 30 bases. ASOs form a double strand with the mRNA, pre-mRNA, or ncRNA targeted by the antisense oligonucleotide, thereby suppressing the function of the mRNA, pre-mRNA, or ncRNA.

[0003] However, ASOs are difficult to put to 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, the oligonucleotide itself, and on 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 bound via a linker, and describes that administration of the ASO suppresses 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 ASO, it was delivered and accumulated in the liver more efficiently than ASO in mice, and expression of a target gene in the liver was suppressed. Patent Document 8 describes an ASO in which a GalNac derivative is bound to HDO via a linker, and describes that when the 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 end of a double-stranded oligonucleotide unit of DNA and RNA suppresses target RNA more efficiently than ASO. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Nature Communications, Volume 6, Article Number 7969 (2015) [Patent documents]

[0009] [Patent Document 1] WO 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 Summary of the Invention [Problem to be solved by the invention]

[0010] When applied as a pharmaceutical to mammals, including humans, in clinical settings, new nucleic acid drugs that can efficiently control the expression of target genes are desired. In addition, when producing double-stranded oligonucleotides (e.g., the above-mentioned HDO and HCDO), a process is required in which the antisense strand and the complementary RNA strand are separately synthesized and then these strands are hybridized at the end. Furthermore, when administered to animals or cells, it is necessary to suppress dissociation into single strands, and it is expected that there may be cases in which it is necessary to work hard to set the handling conditions.

[0011] An object of the present invention is to provide a novel oligonucleotide capable of controlling the expression of a target gene with high efficiency, and an object of the present invention is to provide an oligonucleotide which can be produced more easily than a double-stranded oligonucleotide. [Means for solving the problem]

[0012] The present inventors have found that an oligodeoxyribonucleotide and its complementary strand containing RNA are linked with a linker such as DNA or RNA that is degraded under physiological conditions to form a single-stranded oligonucleotide having a structure that partially hybridizes within a molecule, and that the single-stranded oligonucleotide has an antisense sequence that can control the expression of a target gene, thereby exhibiting an antisense effect equal to or greater than that of a double-stranded oligonucleotide.In addition, since the single-stranded oligonucleotide is single-stranded, there is no hybridization step to form a double strand, and it can be efficiently produced.The present invention encompasses the following aspects. 1. Formula XLY (In the formula, X is a group derived from a first oligonucleotide consisting of 7 to 100 nucleotides which is independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and which contains 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; L is a group derived from a third oligonucleotide which is covalently bonded to the first oligonucleotide and the second oligonucleotide at both ends thereof and which is degraded under physiological conditions; said first oligonucleotide having a nucleotide sequence X and said second oligonucleotide having a nucleotide sequence Y; said nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing with at least a portion of a second oligonucleotide and comprising at least four consecutive nucleotides recognized by RNase H; said 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 and the nucleotide sequence Y comprises at least one 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 a first nucleotide sequence portion and a second nucleotide sequence portion. 2. The single-stranded oligonucleotide according to 1, wherein X comprises at least one sugar-modified nucleotide, and the first nucleotide sequence is the antisense sequence and comprises at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA. 3. The single-stranded oligonucleotide according to 1. or 2., wherein X is bound to L at the 3' side and Y is bound to L at the 5' side. 4. The single-stranded oligonucleotide according to 1. or 2., wherein X is bound to L at the 5' side and Y is bound to L at the 3' side. 5. A single-stranded oligonucleotide according to any one of 1. to 4., wherein the nucleotides contained in the third oligonucleotide are linked to each other by phosphodiester bonds. 6. A single-stranded oligonucleotide according to any one of 1. to 5., wherein the third oligonucleotide is DNA or RNA. 7. A single-stranded oligonucleotide according to any one of 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. A single-stranded oligonucleotide according to any one of 1. to 7., wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' ends of the first nucleotide sequence portion. 9. The single-stranded oligonucleotide of any one of 1. to 8., wherein the first oligonucleotide comprises a phosphorothioate linkage. 10. A single-stranded oligonucleotide according to any one of 1. to 9., wherein the first nucleotide sequence is a sequence of 4 to 20 nucleotides including at least one deoxyribonucleotide. 11. The single-stranded oligonucleotide according to any one of 1. to 10., wherein the second nucleotide sequence is a sequence comprising at least four consecutive nucleotides that are cleaved by RNase H. 12. The single-stranded oligonucleotide according to 11, 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. 13. The single-stranded oligonucleotide according to 11 or 12, 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. 14. The single-stranded oligonucleotide according to any one of 1. to 13., wherein the nucleotide sequence Y comprises at least one antisense sequence. 15. The single-stranded oligonucleotide according to 14, wherein Y has the second nucleotide sequence portion between the antisense sequence portion and L. 16. The single-stranded oligonucleotide according to 14. or 15., wherein the antisense sequence contained in the nucleotide sequence Y is a sequence containing at least 4 consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA. 17. The single-stranded oligonucleotide according to 14. or 15., wherein the antisense sequence portion contained in Y contains at least one sugar-modified nucleotide and does not contain an oligonucleotide strand consisting of four consecutive deoxyribonucleotides. 18. The single-stranded oligonucleotide according to 16. or 17., wherein the nucleotide sequence X is capable of hybridizing with at least a portion of the antisense sequence portion contained in the Y and comprises a sequence comprising at least 4 consecutive nucleotides that are cleaved by RNase H. 19. The single-stranded oligonucleotide according to any one of 1. to 18., wherein X comprises the 5' end or the 3' end. 20. Formula X'-L'- (In the formula, X' is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides which is independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and which contains at least one nucleotide in which at least one of the sugar moiety, the base moiety, and the phosphate moiety has been modified; L' is a group derived from a fifth oligonucleotide which is covalently bonded to the first oligonucleotide and the fourth oligonucleotide at both ends thereof and which is degraded under physiological conditions; The fourth oligonucleotide has an antisense sequence that enables it to hybridize with a target RNA. 19. The single-stranded oligonucleotide according to any one of 1. to 18., further comprising a group represented by: 21. X' comprises at least one sugar-modified nucleotide; 21. The single-stranded oligonucleotide according to 20., wherein the antisense sequence of the fourth oligonucleotide is a sequence containing at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA. 22. The single-stranded oligonucleotide according to claim 20, wherein the antisense sequence portion contained in the fourth oligonucleotide contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. 23. The single-stranded oligonucleotide according to 21. or 22., wherein the antisense sequence portion contained in the fourth oligonucleotide hybridizes with at least a portion of the second oligonucleotide. 24. The single-stranded oligonucleotide according to any one of 20. to 23., wherein the nucleotides contained in the fifth oligonucleotide are linked to each other by phosphodiester bonds. 25. The single-stranded oligonucleotide according to any one of 20. to 24., wherein the fifth oligonucleotide is DNA or RNA. 26. A single-stranded oligonucleotide according to any one of 1. to 25., comprising a sugar-modified nucleotide linked adjacent to at least one of the 5' and 3' ends of the antisense sequence portion. 27. A single-stranded oligonucleotide according to any one of 1. to 26., comprising sugar-modified nucleotides bound adjacent to the 5' and 3' ends of the antisense sequence portion. 28. The single-stranded oligonucleotide according to any one of 1. to 27., wherein the antisense sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide. 29. A single-stranded oligonucleotide according to any one of 1. to 28., wherein the antisense sequence portion contains a phosphorothioate bond. 30. The single-stranded oligonucleotide according to any one of 1. to 29., wherein Y comprises the 5' end or the 3' end. 31. A single-stranded oligonucleotide described in any one of 1. to 30., 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. 32. The single-stranded oligonucleotide according to 31, wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides and proteins, and derivatives thereof. 33. The single-stranded oligonucleotide according to 31. or 32., wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol and tocotrienol. 34. The single-stranded oligonucleotide according to 31. or 32., wherein the functional molecule is a sugar derivative that interacts with an asialoglycoprotein receptor. 35. The single-stranded oligonucleotide according to 31. or 32., wherein the functional molecule is a peptide or protein selected from the group consisting of a receptor ligand and an antibody. 36. A pharmaceutical composition comprising a single-stranded oligonucleotide according to any one of 1. to 35. and a pharmacologically acceptable carrier. 37. A method for regulating the function of a target RNA, comprising a step of contacting a cell with a single-stranded oligonucleotide described in any one of 1. to 35. 38. A method for regulating the function of a target RNA in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a single-stranded oligonucleotide described in any one of 1. to 35. 39. Use of a single-stranded oligonucleotide according to any one of 1. to 35. for controlling the function of a target RNA in a mammal. 40. A method for producing a single-stranded oligonucleotide according to any one of 1. to 35., 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. Effect of the Invention

[0013] According to the present invention, it is possible to provide an oligonucleotide capable of controlling the expression of a target gene with high efficiency, and also to provide an oligonucleotide that can be produced more easily than a double-stranded oligonucleotide (e.g., HDO, HCDO).

[0014] 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 description of the drawings]

[0015] [Figure 1] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Diagram 2] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Diagram 3] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Figure 4] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Diagram 5] This is a conceptual diagram showing one embodiment in which the antisense sequence portion X'2 contained in the first nucleotide sequence portion X2 and X' of a single-stranded oligonucleotide, which is an example of this embodiment, intramolecularly hybridizes with Y2 containing a second nucleotide sequence portion and a sixth nucleotide sequence portion, respectively. [Figure 6]This is a conceptual diagram showing one embodiment in which the antisense sequence portion X'2 contained in the first nucleotide sequence portion X2 and X' of a single-stranded oligonucleotide, which is an example of this embodiment, intramolecularly hybridizes with Y2 containing a second nucleotide sequence portion and a sixth nucleotide sequence portion, respectively. [Figure 7] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Figure 8] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Figure 9] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y0 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Figure 10] This is a conceptual diagram showing an embodiment of a single-stranded oligonucleotide according to the present embodiment, in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of the single-stranded oligonucleotide hybridize intramolecularly, and the antisense sequence portion YZ2 contained in Y and the nucleotide sequence portion X5 contained in X of the single-stranded oligonucleotide hybridize intramolecularly. [Figure 11] This is a conceptual diagram showing an embodiment of a single-stranded oligonucleotide according to the present embodiment, in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of the single-stranded oligonucleotide hybridize intramolecularly, and the antisense sequence portion YZ2 contained in Y and the nucleotide sequence portion X5 contained in X of the single-stranded oligonucleotide hybridize intramolecularly. [Figure 12] This is a conceptual diagram showing an embodiment of a single-stranded oligonucleotide according to the present embodiment, in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of the single-stranded oligonucleotide hybridize intramolecularly, and the antisense sequence portion YZ2 contained in Y and the nucleotide sequence portion X5 contained in X of the single-stranded oligonucleotide hybridize intramolecularly. [Figure 13]This is a conceptual diagram showing an embodiment of a single-stranded oligonucleotide according to the present embodiment, in which the first nucleotide sequence portion X2 and the second nucleotide sequence portion Y0 of the single-stranded oligonucleotide hybridize intramolecularly, and the antisense sequence portion YZ2 contained in Y and the nucleotide sequence portion X5 contained in X of the single-stranded oligonucleotide hybridize intramolecularly. [Figure 14] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Figure 15] FIG. 2 is a conceptual diagram showing one embodiment in which a first nucleotide sequence portion X2 and a second nucleotide sequence portion Y2 of a single-stranded oligonucleotide, which is one example of this embodiment, intramolecularly hybridize. [Figure 16] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of PTEN in mouse brain endothelial cells. [Figure 17] 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 hepatic cancer. [Figure 18] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of ApoB in cells derived from human hepatic 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 mouse brain endothelial cells. [Figure 20] 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 hepatic cancer. [Figure 21] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of ApoB in cells derived from human hepatic cancer. [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 mouse brain endothelial cells. [Figure 23] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. [Figure 24] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. [Diagram 25] 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 hepatic cancer. [Figure 26] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of ApoB in cells derived from human hepatic cancer. [Figure 27] 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 hepatic cancer. [Figure 28] 1 is a graph showing the effect of a single-stranded oligonucleotide according to this embodiment on the expression level of ApoB in mice. [Figure 29] 1 is a graph showing the effect of a single-stranded oligonucleotide according to an embodiment of the present invention on total plasma cholesterol levels in mice. [Diagram 30] 1 is a graph showing the effect of the single-stranded oligonucleotide according to this embodiment on the expression level of Aldolase A in human hepatic cancer-derived cells. [Diagram 31] 1 is a graph showing the effect on ApoB expression levels in the liver of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Diagram 32] 1 is a graph showing the effect on total cholesterol levels in plasma of C57BL / 6J mice administered with a single-stranded oligonucleotide according to this embodiment. [Diagram 33] 1 shows the results of gel electrophoresis before and after hybridization of a single-stranded oligonucleotide according to this embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The terms used in this specification are used in the sense that they are usually 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 it is used alone or together with other terms, unless otherwise specified.

[0017] The term "antisense effect" means that the function of a target RNA selected corresponding to a target gene is controlled by hybridizing with, for example, an oligonucleotide having a sequence complementary to a partial sequence of the target RNA. For example, when the target RNA is an mRNA, it means that the translation of the target RNA is inhibited by hybridization, that the splicing function conversion effect such as exon skipping is caused, and that the target RNA is degraded by the recognition of the hybridized portion. Examples of oligonucleotides that produce the antisense effect include DNA and oligodeoxyribonucleotides, but the oligonucleotides that produce the antisense effect are not limited to these and may be RNA, oligoribonucleotides, or oligonucleotides designed to normally produce the antisense effect.

[0018] "Target RNA" means mRNA, mRNA precursor or ncRNA, and includes mRNA transcribed from genomic DNA encoding a target gene, mRNA with no base modification, mRNA precursor and ncRNA with no splicing, etc. "Target RNA" whose function is controlled by the antisense effect is not particularly limited, and includes RNA related to genes whose expression is enhanced 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.

[0019] "Hybridize" refers to the act of forming a duplex between oligonucleotides or groups derived from oligonucleotides that contain complementary sequences, and the phenomenon in which oligonucleotides or groups derived from oligonucleotides that contain complementary sequences form a duplex.

[0020] "Complementary" means that two nucleic acid bases can form Watson-Crick base pairs (natural base pairs) or non-Watson-Crick base pairs (Hoogsteen base pairs, etc.) through hydrogen bonds. Two oligonucleotides or groups derived from oligonucleotides can "hybridize" when their sequences are complementary. Although two oligonucleotides or groups derived from oligonucleotides do not need to be completely complementary to hybridize, the complementarity for hybridizing two oligonucleotides or groups derived from oligonucleotides 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 by using a computer program that automatically identifies partial sequences of oligonucleotides. For example, OligoAnalyzer is one such software and is 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 groups derived from oligonucleotides can hybridize. Those skilled in the art can also easily design an antisense oligonucleotide complementary to a target RNA, for example, by using a BLAST program or the like based on the information on the nucleotide sequence of the target RNA. For 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), etc.

[0021] The term "group derived from an oligonucleotide" refers to a partial structure of an oligonucleotide formed by removing a hydrogen atom, a hydroxyl group, or the like from at least one of the 3'-terminus and 5'-terminus of an oligonucleotide, in which at least one of the 3'-terminus and 5'-terminus of the oligonucleotide is covalently bonded to another group (e.g., a group derived from an oligonucleotide).

[0022] "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.

[0023] In this specification, whether or not a "nucleotide sequence" contains a nucleotide or an oligonucleotide chain has the same meaning as whether or not the corresponding "nucleotide sequence portion" contains 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.

[0024] "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. A nucleotide sequence being a sequence selected from nucleotides, a sequence of consecutive nucleotides, etc., has the same meaning as a corresponding nucleotide sequence portion being a sequence portion selected from the nucleotides, a sequence portion of the nucleotides, etc.

[0025] "RNaseH" is generally known as a ribonuclease that recognizes a double strand in which DNA and RNA are hybridized, and cleaves the RNA to produce single-stranded DNA. RNaseH is not limited to a double strand in which DNA and RNA are hybridized, but can also recognize a double strand in which at least one of the base moiety, phosphodiester bond moiety, and sugar moiety of at least one of DNA and RNA is modified. For example, RNaseH can also recognize a double strand in which an oligodeoxyribonucleotide and an oligoribonucleotide are hybridized. Therefore, when DNA hybridizes with RNA, it can be recognized by RNase H. The same applies when at least one of the base moiety, the phosphodiester bond moiety, and the sugar moiety is modified in at least one of DNA and RNA. For example, a representative example is an oligonucleotide in which the phosphodiester bond moiety of DNA is modified to phosphorothioate. When RNA hybridizes with DNA, it can be cleaved by RNase H. The same is true 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. 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), The Journal of Biological Chemistry (2004, Vol. 279, No. 35, pp. 36317-36326), etc. The RNase H used in the present invention is preferably mammalian RNase H, more preferably human RNase H, and particularly preferably human RNase H1.

[0026] A "deoxyribonucleotide" is a molecule having a base bound to the carbon atom at the 1' position of 2'-deoxyribose and a phosphate group at the 3' or 5' position. The deoxyribonucleotide in the present invention may be a naturally occurring deoxyribonucleotide, or a deoxyribonucleotide in which the base portion or the phosphodiester bond portion of a naturally occurring deoxyribonucleotide has been modified. Modifications of the base portion or the phosphodiester bond portion may be performed in combination with one deoxyribonucleotide. The modified deoxyribonucleotide is 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. In the present invention, the "deoxyribonucleotide" can also be referred to as a "sugar portion deoxyribonucleotide" or a "sugar portion deoxyribose nucleotide".

[0027] When the "deoxyribonucleotide" constitutes the single-stranded oligonucleotide molecule of the present invention, the 3' position of the deoxyribonucleotide is usually linked to another nucleotide via a phosphodiester bond or a modified phosphodiester bond, and the 5' position of the deoxyribonucleotide is usually linked to another nucleotide via a phosphodiester bond or a modified phosphodiester bond. The 3'-terminal deoxyribonucleotide of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxyl group or a phosphate group at its 3' position, and the 5' position is as described above. The 5'-terminal deoxyribonucleotide of the single-stranded oligonucleotide molecule preferably has a hydroxyl group or a phosphate group at its 5' position, and the 3' position is as described above.

[0028] "Oligodeoxyribonucleotide" refers to an oligonucleotide composed of the above-mentioned deoxyribonucleotides. The deoxyribonucleotides constituting the oligodeoxyribonucleotide may be the same or different.

[0029] "DNA" refers to an oligonucleotide composed of natural deoxyribonucleotides. The natural deoxyribonucleotides that compose DNA may be identical or different.

[0030] A "ribonucleotide" is a molecule having a base bound to the carbon atom at the 1' position of ribose and a phosphate group at the 2', 3', or 5' position. The ribonucleotide in the present invention may be a naturally occurring ribonucleotide or a naturally occurring ribonucleotide in which the base portion or the phosphodiester bond portion has been modified. A single ribonucleotide may be modified in combination with a plurality of modifications of the base portion or the phosphodiester bond portion. The modified ribonucleotide is 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. In the present invention, the "ribonucleotide" can also be referred to as a "sugar portion ribonucleotide" or a "sugar portion ribose nucleotide".

[0031] When the "ribonucleotide" constitutes the single-stranded oligonucleotide molecule of the present invention, typically, the 3' position of the ribonucleotide is linked to another nucleotide via a phosphodiester bond or a modified phosphodiester bond, and the 5' position of the ribonucleotide is linked to another nucleotide via a phosphodiester bond or a modified phosphodiester bond. The 3'-terminal ribonucleotide of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxyl 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 hydroxyl group or a phosphate group at its 5' position, and the 3' position is as described above.

[0032] "Oligoribonucleotide" refers to an oligonucleotide composed of the above-mentioned ribonucleotides. The ribonucleotides constituting the oligoribonucleotide may be the same or different.

[0033] "RNA" refers to an oligonucleotide composed of natural ribonucleotides. The natural ribonucleotides that compose the RNA may be identical or different.

[0034] The term "sugar-modified nucleotide" refers to a nucleotide in which the sugar moiety of the deoxyribonucleotide or ribonucleotide is partially substituted with one or more substituents, or the entire sugar backbone is replaced with a sugar backbone different from ribose and 2'-deoxyribose (e.g., 5- to 6-membered sugar backbone such as hexitol, threose, etc.), or the entire sugar backbone is replaced with a 5- to 6-membered saturated or unsaturated ring (e.g., cyclohexane, cyclohexene, morpholine, etc.) or a partial structure capable of forming a 5- to 6-membered ring by hydrogen bonding (e.g., a peptide structure). The base moiety of the "sugar-modified nucleotide" may be a naturally occurring base or a modified base. The phosphodiester bond moiety of the "sugar-modified nucleotide" may be a phosphodiester bond or a modified phosphodiester bond. A combination of multiple types of modifications of the base moiety or the phosphodiester bond site may be applied to one sugar-modified nucleotide.

[0035] The "sugar-modified nucleotide" may be a bridged nucleotide or a non-bridged nucleotide. Examples of sugar-modified nucleotides include nucleotides disclosed as suitable for use in the antisense method in JP-A-10-304889, WO-2005 / 021570, JP-A-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 the antisense method"), etc. The above-mentioned literature discloses nucleotides such as hexitol nucleotides (HNA), cyclohexene nucleotides (CeNA), peptide nucleic acids (PNA), glycol nucleic acids (GNA), threo nucleotides (TNA), morpholino nucleic acids, tricyclo-DNA (tcDNA), 2'-O-methylated nucleotides, 2'-MOE (2'-O-methoxyethyl)-modified nucleotides, 2'-AP (2'-O-aminopropyl)-modified nucleotides, 2'-fluorinated 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.

[0036] 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 via a phosphodiester bond or a modified phosphodiester bond, and the 5' position of the sugar-modified nucleotide is linked to another nucleotide via a phosphodiester bond or a modified phosphodiester bond. The sugar-modified nucleotide at the 3' end of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxyl 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 the single-stranded oligonucleotide molecule preferably has a hydroxyl group or a phosphate group at its 5' position, and the 3' position is as described above.

[0037] 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).

[0038] 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 specifically, 5-methylation, 5-fluoroation, 5-bromination, 5-iodination, and N4-methylation of cytosine; 2-thiolation, 5-demethylation, 5-fluoroation, 5-bromination, and 5-iodination of thymine; 2-thiolation, 5-fluoroation, 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), and Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365), and these can be used for the base moiety in deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides.

[0039] Examples of modifications of the phosphodiester bond in deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides include, for example, phosphorothioation, methylphosphonation (including chiral-methylphosphonation), methylthiophosphonation, phosphorodithioation, phosphoroamidate, phosphorodiamidate, phosphoroamidothioate, and boranophosphate.

[0040] 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'-fluororation, and 2'-O-methylcarbamoylethylation (MCE), etc.

[0041] A "bridged nucleotide" is a sugar-modified nucleotide in which the bridging unit is substituted by two substitutions in the sugar moiety, for example a 2'- and 4'-bridged nucleotide.

[0042] The 2'- and 4'-bridged nucleotide (2',4'-BNA) may be any nucleotide having a sugar moiety in which the 2'- and 4'-carbon atoms are bridged by two or more atoms, and may be, for example, a C2-6 alkylene group (the alkylene group is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen atoms, oxo groups, and thioxo groups. In addition, one or two methylene groups of the alkylene group are unsubstituted or independently substituted with -O-, -NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group, or a haloC1-6 alkyl group) and a group selected from the group consisting of -S-. By combining the above substitutions and replacements, the group bridging the 2' and 4' positions of 2',4'-BNA is -C(O)-O-, -OC(O)-NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group), -C(O)-NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group), -C(S)-NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group or a halo-C1-6 alkyl group), etc. 1 The sugar-modified nucleotide containing - is -C(O)-NR 1 The nucleotide can be synthesized from a sugar-modified nucleotide containing - or an intermediate thereof using a thiocarbonylation reagent (eg, Lawesson's reagent, etc.) and carrying out protection and deprotection reactions as necessary.

[0043] Examples of such BNAs include locked nucleic acids (registered trademark) also known as LNAs, α-L-methyleneoxy (4'-CH2-O-2') BNAs or β-D-methyleneoxy (4'-CH2-O-2') BNAs, ethyleneoxy (4'-(CH2)2-O-2') BNAs also known as ENAs, β-D-thio (4'-CH2-S-2') BNAs, aminooxy (4'-CH2-ON(R 11 )-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(CH2OCH3)-O-2') BNA, also called cMOE-BNA, amide type BNA (4'-C(O)-N(R 13 )-2')BNA(R 13 may be H or CH3), or other BNAs known to those skilled in the art.

[0044] An "oligonucleotide" is a molecule having a polymerized structure of one or more nucleotides. When an "oligonucleotide" is composed of one nucleotide, the oligonucleotide can be called a "nucleotide."

[0045] "Nucleotide" means a molecule that can be a constituent unit of a nucleic acid (oligonucleotide), and usually has a base as a constituent element. Nucleotides are composed of, for example, a sugar, a base, and a phosphate. Nucleotides include the above-mentioned deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides. The nucleotides contained in the single-stranded oligonucleotide molecule of the present invention are each independently linked to each other via a phosphodiester bond or the above-mentioned modified phosphodiester bond. The 3'-terminal nucleotide of the single-stranded oligonucleotide molecule of the present invention preferably has a hydroxyl group or a phosphate group, more preferably has a hydroxyl group, and usually has a hydroxyl group, at its 3' position. The 5'-terminal nucleotide of the single-stranded oligonucleotide molecule preferably has a hydroxyl group or a phosphate group, more preferably has a hydroxyl group, and usually has a hydroxyl group, at its 5' position.

[0046] "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 nucleotide with a modified sugar moiety.

[0047] The term "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, but the consecutive nucleotides are preferably independently selected from deoxyribonucleotides and sugar-modified nucleotides, and more preferably independently selected from deoxyribonucleotides. The consecutive nucleotides may be the same or different.

[0048] "At least four consecutive nucleotides cleaved by RNaseH" includes four consecutive nucleotides, and is not particularly limited as long as it is cleaved by RNaseH, but includes at least one ribonucleotide. It also preferably includes an oligoribonucleotide, and more preferably includes RNA. It is more preferable that the consecutive nucleotides are independently selected from ribonucleotides. It is also more preferable that the consecutive nucleotides are linked to each other by phosphodiester bonds. The consecutive nucleotides may be the same or different.

[0049] The term "C1-6 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, a t-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, and an isohexyl group.

[0050] The term "C1-6 alkylene group" refers to a divalent substituent obtained by removing one hydrogen atom at any position from the above-mentioned "C1-6 alkyl group", 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.

[0051] The "C2-6 alkylene group" means a straight-chain or branched divalent substituent having 2 to 6 carbon atoms among the above "C1-6 alkylene groups", and examples thereof include an ethylene (ethanediyl) group, a propane-1,3-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.

[0052] "n-" stands for normal, "s-" stands for secondary, and "t-" stands for tertiary.

[0053] The term "C2-20 alkylene group" means a divalent substituent formed by removing one hydrogen atom at any position from a linear or branched saturated hydrocarbon group having 2 to 20 carbon atoms.

[0054] The term "C8-12 alkylene group" means a divalent substituent formed by removing one hydrogen atom at any position from a linear or branched saturated hydrocarbon group having 8 to 12 carbon atoms.

[0055] The term "C2-20 alkenylene group" means a divalent substituent formed by removing one hydrogen atom at any position from a straight-chain or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms.

[0056] The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

[0057] The term "halo C1-6 alkyl group" means a substituent in which a hydrogen atom at any position of the "C1-6 alkyl group" is substituted with one or more halogen atoms independently selected from the group of substituents consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0058] The term "oxo group" refers to a substituent in which an oxygen atom is substituted via a double bond (=O). When an oxo group is substituted for a carbon atom, it forms a carbonyl group together with the carbon atom.

[0059] The term "thioxo group" refers to a substituent in which an oxygen 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.

[0060] The sugar-modified nucleotide is not limited to those exemplified here. Many 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), Journal of Medicinal Chemistry (2016, Vol. 59, No. 21, pp. 9645-9667), Medicinal Chemistry Communications (2014, Vol. 5, pp. 1454-1471) or Future Medicinal Chemistry (2011, Vol. 3, No. 3, pp. 339-365) can also be used as an embodiment of the present invention.

[0061] A person skilled in the art can select and use an appropriate sugar-modified nucleotide from among such sugar-modified nucleotides, taking into consideration aspects such as antisense effect, affinity for a partial sequence of a target RNA, and resistance to nuclease enzymes.

[0062] Next, the antisense sequence, the antisense sequence portion, and the nucleotide sequence portion that intramolecularly hybridizes with the antisense sequence in the present invention will be described.

[0063] The term "antisense sequence" refers to a base sequence of nucleotides constituting an oligonucleotide that is capable of hybridizing with a target RNA.

[0064] The term "antisense sequence portion" refers to a partial structure of a region of an oligonucleotide chain having the antisense sequence.

[0065] In this specification, whether or not an "antisense sequence" contains a nucleotide or an oligonucleotide chain has the same meaning as whether or not the corresponding "antisense sequence portion" contains the nucleotide or the oligonucleotide chain. 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.

[0066] The antisense sequence portion does not need to hybridize with the entire target RNA, but it is sufficient to hybridize with at least a part of the target RNA, but usually hybridizes with at least a part of the target RNA. For example, the expression of the target gene is controlled by hybridizing at least a part of the target RNA with an oligonucleotide (such as DNA, oligodeoxyribonucleotide, or oligonucleotide designed to generate an antisense effect) having an antisense sequence complementary to a partial sequence of the target RNA. In addition, the entire antisense sequence portion does not need to hybridize, and it is not necessary for a part to hybridize, but it is preferable for the entire antisense sequence portion to hybridize.

[0067] 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 part of the target RNA to hybridize, their sequences do not need to be completely complementary, but it is even more preferable that they are completely complementary.

[0068] The antisense sequence is preferably a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized to a target RNA" or a sequence containing "at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides."

[0069] Those skilled in the art can easily determine a nucleotide sequence that matches the antisense sequence "capable of hybridizing with the 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 the target RNA."

[0070] The "at least four consecutive nucleotides recognized by RNase H when hybridized with the 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. Particularly preferably, the consecutive nucleotides are 8 to 10 consecutive deoxyribonucleotides. The consecutive nucleotides may be the same or different from each other.

[0071] In addition, 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'-end and 5'-end nucleotides of the consecutive nucleotides is phosphorothioated.It is more preferable that 80% of the consecutive nucleotides are phosphorothioated, and it is even more preferable that 90% of the consecutive nucleotides are phosphorothioated.It is particularly preferable that all of the consecutive nucleotides are phosphorothioated.

[0072] When the antisense sequence contains "at least four consecutive nucleotides recognized by RNase H when hybridized with the 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 are bound adjacent to at least one of the 3' and 5' sides of the "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA" (antisense sequence portion), more preferably 1 to 7 sugar-modified nucleotides are bound adjacent to at least one of the 3' and 5' sides, and even more preferably 2 to 3 sugar-modified nucleotides are bound adjacent to at least one of the 3' and 5' sides. 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' sides, but it is preferable that the multiple sugar-modified nucleotides are consecutive. It is also preferable that the one or more sugar-modified nucleotides are bound adjacent to both the 3' and 5' sides of the antisense sequence portion. When multiple sugar-modified nucleotides are bound adjacently to at least one of the 3' and 5' ends of the antisense sequence portion, "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, the respective sugar-modified nucleotides may be the same or different.

[0073] The sugar-modified nucleotide moiety 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 to the target RNA, but it is preferable that it hybridizes to the target RNA from the same viewpoint as above.

[0074] From the viewpoint of excellent pharmacokinetics, it is preferable that at least one of the sugar-modified nucleotides located on the 3' side and the 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. It is also preferable that all of them are phosphorothioated. When multiple sugar-modified nucleotides are located on the 3' side, it is preferable that the bonds between the nucleotides are phosphorothioated, and the same applies when multiple sugar-modified nucleotides are located on the 5' side.

[0075] At least a portion of the "at least four consecutive nucleotides recognized by RNase H when hybridized to a target RNA" may or may not hybridize intramolecularly. 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 a target RNA" may or may not hybridize intramolecularly.

[0076] 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, and may or may not contain deoxyribonucleotides, but it contains at least one sugar-modified nucleotide and not containing 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 content of sugar-modified nucleotides is, for example, 25% or more. From the viewpoint of increasing affinity for a partial sequence of a target RNA or resistance to nuclease, the content of sugar-modified nucleotides is preferably 30% or more, more preferably 50% or more. From the same viewpoint, it is preferable that at least one of the 3'-side nucleotide and the 5'-side nucleotide of this antisense sequence portion is a sugar-modified nucleotide, and it is more preferable that the 3'-side nucleotide and the 5'-side nucleotide are sugar-modified nucleotides. In another embodiment, the content of sugar-modified nucleotides in the antisense sequence portion is preferably 100%.

[0077] It is more preferable that the antisense sequence portion "containing at least one sugar-modified nucleotide and not containing an oligonucleotide strand consisting of four consecutive deoxyribonucleotides" does not contain an oligonucleotide strand consisting of three consecutive deoxyribonucleotides.

[0078] The antisense sequence portion (mixmer) "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" is usually 4 to 30 consecutive nucleotides, preferably 8 to 25 consecutive nucleotides, more preferably 10 to 20 consecutive nucleotides, even more preferably 14 to 16 consecutive nucleotides, and particularly preferably 15 consecutive nucleotides. These consecutive nucleotides may be the same or different.

[0079] 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 nucleotides at the 3'-end and 5'-end of the antisense sequence portion is phosphorothioated. It is more preferable that 80% of the bonds between nucleotides contained in the antisense sequence portion are phosphorothioated, even more preferable that 90% are phosphorothioated, and particularly preferable that all are phosphorothioated.

[0080] At least a part 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 hybridize intramolecularly, but it is preferable that it does not hybridize intramolecularly. Therefore, it is preferable that the single-stranded oligonucleotide molecule has the antisense sequence portion in the order of the antisense sequence portion (mixmer), the first nucleotide sequence portion, L, and the second nucleotide sequence portion, and the number of nucleotides contained in Y is set so that the antisense sequence portion does not hybridize intramolecularly, or the single-stranded oligonucleotide molecule has the antisense sequence portion in the order of the first nucleotide sequence portion, L, the second nucleotide sequence portion, and the antisense sequence portion (mixmer), and the number of nucleotides contained in X (and X') is set so that the antisense sequence portion does not hybridize intramolecularly. It is preferable that the difference between the number of nucleotides contained in the single-stranded oligonucleotide molecule between the 5'-end of L and the 5'-end of the single-stranded oligonucleotide molecule and the number of nucleotides contained in the single-stranded oligonucleotide molecule between the 3'-end of L and the 3'-end of the single-stranded oligonucleotide molecule is close to the number of nucleotides contained in the antisense sequence portion, and the difference is usually 6 to 30, preferably 8 to 25, more preferably 10 to 20, even more preferably 14 to 16 consecutive nucleotides, and particularly preferably 15 consecutive nucleotides.

[0081] It is not necessary that 1 to 10 sugar-modified nucleotides 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", but they may be bound thereto. In this case, the one or more sugar-modified nucleotides are similar to the sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA", and may or may not hybridize intramolecularly, but it is preferable that they do not hybridize intramolecularly.

[0082] The "sugar-modified nucleotide" contained in the antisense sequence portion may be a nucleotide having an increased affinity for a partial sequence of a target RNA or an increased resistance to nucleases due to substitution or the like, but is preferably a 2'-O-methylated nucleotide, a 2'-MOE (2'-O-methoxyethyl)-modified nucleotide, a 2'-AP (2'-O-aminopropyl)-modified nucleotide, a 2'-fluorinated nucleotide, a 2'-F-arabinonucleotide (2'-F-ANA), a bridged nucleotide (BNA (Bridged Nucleic Acid)) or a 2'-O-methylcarbamoylethylated nucleotide (MCE), more preferably a BNA or a 2'-O-methylated nucleotide, even more preferably an LNA containing a partial structure represented by the following formula (I) or a 2'-O-methylated nucleotide, and particularly preferably an LNA. 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.

[0083] [ka]

[0084] 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. In addition, the purin-9-yl group and the 2-oxo-pyrimidin-1-yl group also include their respective tautomers.

[0085] The type, number and position of sugar-modified nucleotides, deoxyribonucleotides and ribonucleotides in the antisense sequence portion may affect the antisense effect of the single-stranded oligonucleotide disclosed herein. The type, number and position of the sugar-modified nucleotides vary depending on the sequence of the target RNA, and cannot be generally stated, but a person skilled in the art can determine a preferred embodiment while taking into consideration the descriptions in the literature on the antisense method. In addition, the antisense effect of the single-stranded oligonucleotide after modification of the base portion, sugar portion or phosphodiester bond portion is 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 single-stranded oligonucleotide after modification 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 exerted by 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, 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.

[0086] At least two nucleotides on either the 3' or 5' side of the antisense sequence portion "containing at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" are preferably sugar-modified nucleotides, and the sugar-modified nucleotides are preferably bridged nucleotides, and particularly preferably LNA. When the two nucleotides on the 3' side of the antisense sequence portion are sugar-modified nucleotides, it is preferable that two or more of the three nucleotides on the 5' side are sugar-modified nucleotides, and are linked in any of the following orders from the terminal side of the antisense sequence portion. When the two nucleotides on the 5' side of the antisense sequence portion are sugar-modified nucleotides, it is preferable that two or more of the three nucleotides on the 3' side are sugar-modified nucleotides, and are linked in any of the following orders from the terminal side of the antisense sequence portion. In these orders, the left side is the terminal side of the antisense sequence portion, and the right side is the inside of the antisense sequence portion. The sugar-modified nucleotides are preferably bridged nucleotides, and 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

[0087] When a single-stranded oligonucleotide contains a nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion, the type, number, and modification position 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 and the like exerted by the single-stranded oligonucleotide. The preferred embodiment differs depending on the type, sequence, etc. of the nucleotide to be modified, so it cannot be generally stated, but it can be specified by measuring the antisense effect of the single-stranded oligonucleotide after modification, as with the above-mentioned antisense sequence portion. 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 a specific cell to generate an oligonucleotide containing the antisense sequence portion and easily exert the antisense effect, the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" preferably contains "at least four consecutive nucleotides that are cleaved by RNase H", and preferably contains at least one ribonucleotide. In addition, it is preferable that it contains an oligoribonucleotide, and more preferably that it 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, and the consecutive nucleotides may be the same or different.

[0088] 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). In order for the antisense sequence portion and the "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" to hybridize, their sequences do not need to be completely complementary, but may be completely complementary. In addition, the entire "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" does not need to hybridize to the antisense sequence portion, and a part of it may not hybridize, but the entirety 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 the stability of the intramolecularly hybridized structure, the strength of the antisense effect on the target RNA, and other factors such as cost, synthesis yield, etc.

[0089] Next, X, X', and Y in the present invention will be described. There are several embodiments of the present invention, but first, common points will be described.

[0090] 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 sugar moiety, the base moiety, and the phosphate moiety. The first oligonucleotide comprises at least one nucleotide having at least one modified sugar moiety, the base moiety, and the phosphate moiety. The first oligonucleotide has a nucleotide sequence X, and the nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing with at least a portion of the second oligonucleotide and comprising at least four consecutive nucleotides recognized by RNase H.

[0091] 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.

[0092] The number of nucleotides contained in X is 7 to 100, and preferably 7 to 50. 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, the cost, and the synthesis yield. Details will be described later.

[0093] 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 at least one of the sugar moiety, the base moiety and the phosphate moiety is modified. 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 including at least one ribonucleotide.

[0094] 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.

[0095] 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, the cost, and the synthesis yield. Details will be described later.

[0096] X and Y hybridize intramolecularly at the first nucleotide sequence portion and the second nucleotide sequence portion.

[0097] 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.

[0098] 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.

[0099] The first nucleotide sequence preferably contains 4 to 25 consecutive nucleotides, more preferably 8 to 20 consecutive nucleotides. In order for the single-stranded oligonucleotide to be recognized by intracellular RNase H, the first nucleotide sequence is preferably a sequence independently selected from deoxyribonucleotides and sugar-modified nucleotides, more preferably a sequence of consecutive deoxyribonucleotides. The consecutive nucleotides may be the same or different.

[0100] In addition, 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'-side and 5'-side 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 by phosphorothioate bonds. More details will be described later.

[0101] The second nucleotide sequence preferably contains at least 4 consecutive nucleotides that are cleaved by RNaseH, more preferably contains 4 to 25 consecutive nucleotides, and even more preferably contains 8 to 22 consecutive nucleotides. These consecutive nucleotides may be the same or different. Since the second nucleotide sequence portion is cleaved by RNaseH in cells, the second nucleotide sequence portion preferably contains an oligoribonucleotide, more preferably contains RNA. It is particularly preferred that the nucleotides contained in the second nucleotide sequence portion are linked to each other by phosphodiester bonds. Further details will be described later.

[0102] At least one of nucleotide sequence X and nucleotide sequence Y comprises an antisense sequence capable of hybridizing with at least a portion of a target RNA.

[0103] X' 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 one of the sugar moiety, the base moiety, and the phosphate moiety. The fourth oligonucleotide comprises at least one nucleotide having at least one modified sugar moiety, the base moiety, and the phosphate moiety. The fourth oligonucleotide has a nucleotide sequence X', and the nucleotide sequence X' comprises a fourth nucleotide sequence that is an antisense sequence that allows hybridization with a target RNA.

[0104] Nucleotide sequence X' is a base sequence of nucleotides constituting the fourth oligonucleotide, and includes a fourth nucleotide sequence. The fourth nucleotide sequence is a base sequence of nucleotides constituting the fourth nucleotide sequence portion.

[0105] The number of nucleotides contained in X' is 7 to 100, with the lower limit being preferably 8, more preferably 10, even more preferably 12, and even more preferably 13. The upper limit of the number of nucleotides contained in X' is preferably 50, more preferably 35, even more preferably 25, and even more preferably 20. The number of nucleotides contained in X' is preferably 10 to 50, more preferably 10 to 35, even more preferably 12 to 25 bases, even more preferably 13 to 20 bases, and particularly preferably 14 to 15. 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 hybridized structure within the molecule, costs, and synthesis yield.

[0106] The type, number and modification position of sugar-modified nucleotides, deoxyribonucleotides and ribonucleotides in X may affect the antisense effect and the like exerted by the single-stranded oligonucleotide. The preferred embodiment differs depending on the type and sequence of the nucleotide to be modified, and cannot be generally stated, but can be specified by measuring the antisense effect of the single-stranded oligonucleotide after modification, as in the case of the antisense sequence portion described above. Y and X' are also the same as X.

[0107] When two or more of X', Y, and X hybridize to the same target RNA, the antisense sequences they have may be the same or different. X', Y, and X may hybridize to different target RNAs.

[0108] When nucleotide sequence X has an antisense sequence, the antisense sequence preferably contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA" or "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," and more preferably contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA." When the first nucleotide sequence is an antisense sequence, the antisense sequence is a sequence that contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA."

[0109] When nucleotide sequence Y has an antisense sequence, the antisense sequence preferably contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA" or "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," and more preferably contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA." The same applies when nucleotide sequence X' contains an antisense sequence.

[0110] 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, which makes it easier to exert an antisense effect. From this viewpoint, it is preferable that the antisense sequence portion contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA."

[0111] When nucleotide sequence X has an antisense sequence, Y may contain a "nucleotide sequence portion that hybridizes intramolecularly with the antisense sequence portion" (eighth nucleotide 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.

[0112] When the nucleotide sequence X' has an antisense sequence, Y may contain a "nucleotide sequence portion that intramolecularly hybridizes to the antisense sequence portion" (sixth nucleotide sequence portion).

[0113] When nucleotide sequence Y has an antisense sequence, X may contain a "nucleotide sequence portion that intramolecularly hybridizes to the antisense sequence portion" (seventh nucleotide sequence portion).

[0114] Next, the following will explain each of the cases: [A] where nucleotide sequence X contains an antisense sequence, and [B] where nucleotide sequence Y contains an antisense sequence.

[0115] [A] When nucleotide sequence X contains an antisense sequence When the nucleotide sequence X includes an antisense sequence, it is preferable that the first nucleotide sequence is the antisense sequence. In another embodiment, it is preferable that the X has a first nucleotide sequence portion between the antisense sequence portion and L. The following will explain the embodiments of the present invention in order, but the embodiments are not limited thereto. For example, the first nucleotide sequence may partially overlap with the antisense sequence.

[0116] [A-1] When the first nucleotide sequence is an antisense sequence When the first nucleotide sequence is an antisense sequence, the first nucleotide sequence that is the antisense sequence is a sequence that contains "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA". Preferred aspects of the first nucleotide sequence and the first nucleotide sequence portion are the same as the sequence that contains "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA" described in the antisense sequence and the antisense sequence portion. In addition, it is preferable that 1 to 10 sugar-modified nucleotides are bound adjacent to at least one of the 3' side and the 5' side 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' side and the 5' side of "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA" (antisense sequence portion).

[0117] Furthermore, when the single-stranded oligonucleotide contains a partial structure of X'-L'-X, the fourth nucleotide sequence, which is an antisense sequence contained in the nucleotide sequence X', is preferably a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA" or a sequence containing "at least one sugar-modified nucleotide and not containing an oligonucleotide chain consisting of four consecutive deoxyribonucleotides", and more preferably a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA". The preferred form etc. of the antisense sequence contained in the nucleotide sequence X' is the same as that described above for the antisense sequence and the 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.

[0118] In addition to the characteristics described in the common points above, the first nucleotide sequence preferably contains 4 to 20 consecutive nucleotides, more preferably contains 5 to 16 consecutive nucleotides, even more preferably contains 6 to 12 consecutive nucleotides, even more preferably contains 8 to 10 consecutive nucleotides, and particularly preferably contains 8 to 10 consecutive deoxyribonucleotides.

[0119] In one embodiment, the lower limit of the number of nucleotides contained in X is preferably 8, more preferably 10, even more preferably 12, and even more preferably 13. The upper limit of the number of nucleotides contained in X is preferably 50, more preferably 35, even more preferably 25, and even more preferably 20. The number of nucleotides contained in X is preferably 10 to 50, more preferably 10 to 35, even more preferably 12 to 25, even more preferably 13 to 20, and particularly preferably 13 to 15.

[0120] In one embodiment, the difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0.

[0121] Furthermore, when a single-stranded oligonucleotide contains a partial structure of X'-L'-X, in one embodiment, the difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0. The number of nucleotides contained in X' is as described above as a common point.

[0122] When the single-stranded oligonucleotide contains a partial structure of X'-L'-X, in another embodiment, the difference between the number of nucleotides contained in X'-L'-X and the number of nucleotides contained in Y is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0. The number of nucleotides contained in X' is as described above as a common point.

[0123] In this case, in addition to the second nucleotide sequence, Y may further include a sixth nucleotide sequence that allows hybridization with the fourth nucleotide sequence portion and contains at least one ribonucleotide, and may further include a tenth nucleotide sequence that allows hybridization with L', which is a group derived from the fifth oligonucleotide. That is, Y may be a combination of the second nucleotide sequence portion and the sixth nucleotide sequence portion linked in this order, or a combination of the second nucleotide sequence portion, the tenth nucleotide sequence portion, and the sixth nucleotide sequence portion linked in this order. A preferred embodiment of the sixth nucleotide sequence is the same as the second nucleotide sequence described below. A preferred embodiment of the tenth nucleotide sequence portion is the same as L' described below.

[0124] In this case, as described below, at least one of the 5' and 3' ends of the second nucleotide sequence portion may be linked to the adjacent nucleotide via a phosphorothioate bond, but in this case it is preferably linked via a phosphodiester bond. At least one of the 5' and 3' ends of the second nucleotide sequence portion may be linked to one or more sugar-modified nucleotides adjacent thereto, but in this case it is preferable that they are not linked. At least one of the 5' and 3' ends of the sixth nucleotide sequence portion is preferably linked to the adjacent nucleotide via a phosphorothioate bond, and the embodiment is the same as in the case of the second nucleotide sequence described below. At least one of the 5' and 3' ends of the sixth nucleotide sequence portion is preferably linked to one or more sugar-modified nucleotides adjacent thereto, and the embodiment is the same as in the case of the second nucleotide sequence described below.

[0125] In addition to the common points described above, the second nucleotide sequence preferably contains 4 to 20 consecutive nucleotides, more preferably contains 5 to 16 consecutive nucleotides, even more preferably contains 6 to 12 consecutive nucleotides, even more preferably contains 8 to 12 consecutive nucleotides, and particularly preferably contains 10 to 12 consecutive nucleotides.

[0126] Until the single-stranded oligonucleotide is delivered into the nucleus of a specific cell, degradation by an RNA degrading enzyme such as RNaseA is suppressed, and in a specific cell, a group derived from the second oligonucleotide is degraded by a nuclease such as RNaseH to generate an oligonucleotide that is at least a part of the first oligonucleotide and includes the antisense sequence portion, so that the antisense effect is easily exerted. In this respect, it is preferable that at least one of the 5' side and the 3' side of the second nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond. When Y is linked to L at the 5' side, it is more preferable that the 3' side of the second nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond, and when Y is linked to L at the 3' side, it is more preferable that the 5' side of the second nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond. In addition, in terms of suppressing degradation by an enzyme such as an RNA degrading enzyme, it is preferable that 1 to 10 sugar-modified nucleotides are linked adjacent to at least one of the 5' side and the 3' side of the second nucleotide sequence portion. When Y is bound to L at the 5' side, it is more preferred that 1 to 7 sugar-modified nucleotides are bound adjacent to the 3' side of the second nucleotide sequence portion, and even more preferred that 2 or 3 sugar-modified nucleotides are bound. When Y is bound to L at the 3' side, it is more preferred that 1 to 7 sugar-modified nucleotides are bound adjacent to the 5' side of the second nucleotide sequence portion, and even more preferred 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 preferred 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' sides of the second nucleotide sequence portion, "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' sides of the second nucleotide sequence portion, each sugar-modified nucleotide may be the same or different.

[0127] 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.

[0128] The sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of the second nucleotide sequence portion is preferably a 2'-O-methylated nucleotide, a 2'-MOE (2'-O-methoxyethyl)-modified nucleotide, a 2'-AP (2'-O-aminopropyl)-modified nucleotide, a 2'-fluorinated nucleotide, a 2'-F-arabinonucleotide (2'-F-ANA), a bridged nucleotide (BNA (Bridged Nucleic Acid)) or a 2'-O-methylcarbamoylethylated nucleotide (MCE), more preferably a BNA or a 2'-O-methylated nucleotide, even more preferably an LNA containing a partial structure represented by the following formula (I) or a 2'-O-methylated nucleotide, and particularly preferably a 2'-O-methylated nucleotide.

[0129] [ka]

[0130] 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.

[0131] The number of nucleotides in the oligonucleotide adjacent to at least one of the 5' and 3' sides 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' and 3' sides 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 the 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 an 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.

[0132] In another embodiment, when nucleotide sequence Y further contains an antisense sequence, it is preferable that the Y has a second nucleotide sequence portion between the antisense sequence portion and L. The sequence of the antisense sequence portion is the same as the antisense sequence contained in nucleotide sequence Y in [B] When nucleotide sequence Y contains an antisense sequence, which will be described later.

[0133] When nucleotide sequence Y includes an antisense sequence, the second nucleotide sequence is the same as the second nucleotide sequence described below in [B] When nucleotide sequence Y includes an antisense sequence, in addition to the second nucleotide sequence described in the common points. When the first nucleotide sequence is an antisense sequence and nucleotide sequence Y includes an antisense sequence, the second nucleotide sequence preferably includes 4 to 25 consecutive nucleotides, more preferably includes 10 to 25 consecutive nucleotides, even more preferably includes 12 to 22 consecutive nucleotides, and particularly preferably includes 12 to 18 consecutive nucleotides.

[0134] The mode of the nucleotide bound adjacent to the second nucleotide sequence portion and the bond with the nucleotide are the same as those in the case where nucleotide sequence Y contains an antisense sequence (B) described below.

[0135] When nucleotide sequence Y includes an antisense sequence, in one embodiment, the number of nucleotides included in X is preferably 10 to 35, more preferably 12 to 25, even more preferably 12 to 16, and particularly preferably 14 to 15. The number of nucleotides contained in Y is preferably as large as the number of nucleotides contained in the "antisense sequence portion contained in Y" compared to the number of nucleotides contained in X. The difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably 6 to 30, more preferably 8 to 25, even more preferably 10 to 20, and even more preferably 13 to 15.

[0136] When nucleotide sequence Y includes an antisense sequence, in another embodiment, the number of nucleotides included in X is preferably 20 to 40, more preferably 24 to 38, even more preferably 26 to 38, even more preferably 28 to 33, and even more preferably 30 to 32.

[0137] In this case, the difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0.

[0138] In this case, the nucleotide sequence X may further comprise a seventh nucleotide sequence comprising at least one ribonucleotide, which allows hybridization with the antisense sequence portion comprised by Y. When the nucleotide sequence X comprises the seventh nucleotide sequence, the single-stranded oligonucleotide represented by the formula XLY comprises the seventh nucleotide sequence portion, the first nucleotide sequence portion, L, the second nucleotide sequence portion, and the antisense sequence portion comprised by Y, in this order.

[0139] A preferred embodiment of the seventh nucleotide sequence portion is the same as the "nucleotide sequence portion that intramolecularly hybridizes with the antisense sequence portion". In particular, the seventh nucleotide sequence preferably contains 10 to 20 nucleotides, more preferably contains 12 to 19 nucleotides, and further preferably contains 13 to 15 ribonucleotides.

[0140] Until the single-stranded oligonucleotide is delivered into the nucleus of a specific cell, degradation by an RNA degrading enzyme such as RNaseA is suppressed, and in a specific cell, a group derived from the second oligonucleotide is degraded by a nuclease such as RNaseH to generate an oligonucleotide that is at least a part of the first oligonucleotide and includes the antisense sequence portion, and further, an oligonucleotide that is at least a part of the second oligonucleotide and includes the antisense sequence portion included by Y is generated, and from the viewpoint of easily exerting an antisense effect, it is preferable that at least one of the 5' side and the 3' side of the seventh nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond. When X is linked to L at the 5' side, it is more preferable that the 3' side of the seventh nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond, and when X is linked to L at the 3' side, it is more preferable that the 5' side of the seventh nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond. From the viewpoint of suppressing degradation by enzymes such as RNase, it is preferable that 1 to 10 sugar-modified nucleotides are bound adjacent to at least one of the 5' and 3' sides of the seventh 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 seventh nucleotide sequence portion, and even more preferable that 2 or 3 sugar-modified nucleotides are bound adjacent to the 3' side of the seventh nucleotide sequence portion. 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 seventh nucleotide sequence portion, and even more preferable that 2 or 3 sugar-modified nucleotides are bound adjacent to the 5' side of the seventh nucleotide sequence portion. Here, a plurality of deoxyribonucleotides or ribonucleotides or both may be contained between the plurality of sugar-modified nucleotides at least one of the 3' and 5' sides, but it is preferable that the plurality of sugar-modified nucleotides are consecutive.When multiple sugar-modified nucleotides are bound adjacent to at least one of the 3' and 5' ends of the seventh nucleotide sequence portion, "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 adjacent to at least one of the 3' and 5' ends of the seventh nucleotide sequence portion, each sugar-modified nucleotide may be the same or different.

[0141] The sugar-modified nucleotide portion bound adjacent to at least one of the 3' and 5' sides of the seventh 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. The number of nucleotides in the oligonucleotide adjacent to at least one of the 5' and 3' sides of the seventh 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' and 3' sides of the antisense sequence portion contained by Y, 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 seventh 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 5' side of the antisense sequence portion contained by Y, 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 seventh 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 bound adjacent to the 3' side of the antisense sequence portion contained by Y, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same.

[0142] The form of the sugar-modified nucleotide moiety bound adjacent to at least one of the 3' and 5' sides of the seventh nucleotide sequence portion is the same as the sugar-modified nucleotide moiety bound adjacent to at least one of the 3' and 5' sides of the second nucleotide sequence portion.

[0143] [A-2] When X has a first nucleotide sequence portion between the antisense sequence portion and L The first nucleotide sequence portion and the antisense sequence portion may be directly linked to each other, or indirectly linked to each other via an oligonucleotide therebetween, but it is preferable that they are indirectly linked to each other via an oligonucleotide.

[0144] The antisense sequence may be a sequence that contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA," or a sequence that "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," but the antisense sequence is preferably a sequence that contains "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA." The preferred form of the sequence is the same as that described above for the antisense sequence and the 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.

[0145] When the antisense sequence is a sequence containing "at least four consecutive nucleotides recognized by RNase H when hybridized with a target RNA" and the first nucleotide sequence portion and the antisense sequence portion are indirectly linked via an oligonucleotide, the oligonucleotide preferably contains one or more sugar-modified nucleotides adjacent to and linked to at least one of the 3' and 5' ends of the antisense sequence portion. The sugar-modified nucleotides are as described above. The oligonucleotide preferably further contains an oligonucleotide that is degraded under physiological conditions. The oligonucleotide that is degraded under physiological conditions is similar to L' described below. Therefore, the first oligonucleotide preferably has the first nucleotide sequence portion, a group derived from the oligonucleotide that is degraded under physiological conditions, the one or more sugar-modified nucleotides, the antisense sequence portion contained in X, and the one or more sugar-modified nucleotides in this order.

[0146] When the antisense sequence "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides" and the first nucleotide sequence portion and the antisense sequence portion contained in X are indirectly bound via an oligonucleotide, the oligonucleotide is preferably an oligonucleotide that is degraded under physiological conditions. The embodiment of the oligonucleotide that is degraded under physiological conditions is the same as L' described below.

[0147] Furthermore, when the single-stranded oligonucleotide contains a partial structure of X'-L'-X, the fourth nucleotide sequence, which is an antisense sequence contained in the nucleotide sequence X', is the same as the fourth nucleotide sequence described in [A-1].

[0148] In addition to the above common points, the first nucleotide sequence preferably contains 8 to 17 consecutive nucleotides, and more preferably contains 8 to 10 consecutive nucleotides.

[0149] In addition to the above common points, the second nucleotide sequence preferably contains 4 to 20 consecutive nucleotides, more preferably 8 to 19 consecutive nucleotides, and even more preferably 9 to 11 consecutive nucleotides.

[0150] The sugar-modified nucleotide moiety bound adjacent to at least one of the 3' and 5' sides of the second nucleotide sequence portion is the same as the sugar-modified nucleotide moiety bound adjacent to at least one of the 3' and 5' sides of the second nucleotide sequence described in detail in [A-1] above.

[0151] The number of nucleotides contained in X is preferably 10 to 50, more preferably 20 to 40, even more preferably 20 to 30, still more preferably 22 to 28, and particularly preferably 25 to 28.

[0152] In one embodiment, the number of nucleotides contained in Y is preferably 4 to 25, more preferably 8 to 20, further preferably 10 to 20, and particularly preferably 10 to 16. In this case, the number of nucleotides contained in X is greater than the number of nucleotides contained in Y, and the difference is preferably close to the number of nucleotides contained in the antisense sequence portion, and is preferably 6 to 30, more preferably 8 to 25, even more preferably 10 to 20, and even more preferably 12 to 15.

[0153] In another embodiment, the number of nucleotides contained in Y is preferably 10 to 50, more preferably 20 to 40, even more preferably 20 to 30, still more preferably 22 to 28, and particularly preferably 25 to 28.

[0154] In this case, the difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0.

[0155] In this case, in addition to the second nucleotide sequence portion, Y may further comprise an eighth nucleotide sequence portion containing at least one ribonucleotide that allows hybridization with the antisense sequence portion of X, or may further comprise a ninth nucleotide sequence portion that allows hybridization with an oligonucleotide linking the first nucleotide sequence portion and the antisense sequence portion of X. That is, Y may be the second nucleotide sequence portion and the eighth nucleotide sequence portion linked in this order, or the second nucleotide sequence portion, the ninth nucleotide sequence portion and the eighth nucleotide sequence portion linked in this order.

[0156] A preferred embodiment of the eighth nucleotide sequence portion is the same as the "nucleotide sequence portion that intramolecularly hybridizes with the antisense sequence portion" and the same as the second nucleotide sequence portion. The embodiment of the sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the eighth nucleotide sequence portion is similar to 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. The sugar-modified nucleotide moiety bound adjacent to at least one of the 3'-side and 5'-side of the eighth nucleotide sequence portion may or may not hybridize to a part of the first oligonucleotide, but preferably hybridizes to a part of the first oligonucleotide. The number of nucleotides in the oligonucleotide chain containing one or more sugar-modified nucleotides adjacent to at least one of the 5'-side and 3'-side of the eighth 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 adjacent to at least one of the 5'-side and 3'-side of the antisense sequence portion contained by X, 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 eighth nucleotide sequence portion, the number of nucleotides may be the same as or different from the number of nucleotides in an oligonucleotide chain comprising one or more sugar-modified nucleotides bound adjacent to the 5' side of the antisense sequence portion contained by X, 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 5' side of the eighth nucleotide sequence portion, the number of nucleotides may be the same as or different from the number of nucleotides in an oligonucleotide chain comprising one or more sugar-modified nucleotides bound adjacent to the 3' side of the antisense sequence portion contained by X, but the difference is preferably within 3, more preferably within 1, and particularly preferably the same.

[0157] In this case, at least one of the 5' and 3' ends of the second nucleotide sequence may be linked to the adjacent nucleotide via a phosphorothioate bond, but is preferably linked via a phosphodiester bond. In addition, at least one of the 5' and 3' ends of the second nucleotide sequence may be linked to one or more sugar-modified nucleotides adjacent to the second nucleotide sequence, but is preferably not linked to the second nucleotide sequence. A preferred embodiment of the ninth nucleotide sequence portion is the same as L' described below.

[0158] Furthermore, when the single-stranded oligonucleotide contains a partial structure of X'-L'-X, in one embodiment, the difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0. When the single-stranded oligonucleotide contains a partial structure of X'-L'-X, in another embodiment, the difference between the number of nucleotides contained in X'-L'-X and the number of nucleotides contained in Y is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0. In this case, in addition to the second nucleotide sequence portion, Y may further include a sixth nucleotide sequence portion that is capable of hybridizing with the fourth nucleotide sequence portion and contains at least one ribonucleotide, and may further include a tenth nucleotide sequence portion that is capable of hybridizing with L', which is a group derived from the fifth oligonucleotide. That is, Y may be a combination of the second nucleotide sequence portion, the eighth nucleotide sequence portion, and the sixth nucleotide sequence portion linked in this order, a combination of the second nucleotide sequence portion, the eighth nucleotide sequence portion, the tenth nucleotide sequence portion, and the sixth nucleotide sequence portion linked in this order, a combination of the second nucleotide sequence portion, the ninth nucleotide sequence portion, the eighth nucleotide sequence portion, and the sixth nucleotide sequence portion linked in this order, or a combination of the second nucleotide sequence portion, the ninth nucleotide sequence portion, the eighth nucleotide sequence portion, the tenth nucleotide sequence portion, and the sixth nucleotide sequence portion linked in this order. The sixth nucleotide sequence is the same as the sixth nucleotide sequence described in [A-1] above. The eighth nucleotide sequence and the ninth nucleotide sequence are as described above.

[0159] In this case, at least one of the 5' and 3' ends of the second nucleotide sequence portion may be linked to the adjacent nucleotide via a phosphorothioate bond, but in this case it is preferably linked to a phosphodiester bond. At least one of the 5' and 3' ends of the second nucleotide sequence portion may be linked to one or more sugar-modified nucleotides adjacent to the nucleotide, but in this case it is preferably not linked. Similarly, at least one of the 5' and 3' ends of the eighth nucleotide sequence portion may be linked to the adjacent nucleotide via a phosphorothioate bond, but in this case it is preferably linked to a phosphodiester bond. At least one of the 5' and 3' ends of the eighth nucleotide sequence portion may be linked to one or more sugar-modified nucleotides adjacent to the nucleotide, but in this case it is preferably not linked. At least one of the 5' and 3' ends of the sixth nucleotide sequence portion is preferably linked to the adjacent nucleotide via a phosphorothioate bond, and the embodiment is the same as that of the second nucleotide sequence described in detail in [A-1] above. It is preferable that one or more sugar-modified nucleotides are bound adjacent to at least one of the 5' and 3' sides of the sixth nucleotide sequence portion, the details of which are the same as those of the second nucleotide sequence described in detail above in [A-1].

[0160] Furthermore, when nucleotide sequence Y includes an antisense sequence, it is preferable that Y has a second nucleotide sequence portion between the antisense sequence portion and L, and the antisense sequence portion is the same as the case where nucleotide sequence Y includes an antisense sequence described below in [B].

[0161] In this case, the mode of the second nucleotide sequence portion is the same as the mode of the second nucleotide sequence portion described in [A-1] when nucleotide sequence Y further includes an antisense sequence. The mode of the nucleotide bound adjacent to the second nucleotide sequence portion and the bond with the nucleotide are the same as the mode of the second nucleotide sequence portion when nucleotide sequence Y includes an antisense sequence described later in [B].

[0162] In this case, nucleotide sequence X may further comprise a seventh nucleotide sequence which is capable of hybridizing to the portion of the antisense sequence comprised by Y and which comprises at least one ribonucleotide.

[0163] In this case, in one embodiment, the single-stranded oligonucleotide represented by the formula XLY has an antisense sequence portion comprised by X, a seventh nucleotide sequence portion, a first nucleotide sequence portion, L, a second nucleotide sequence portion, and an antisense sequence portion comprised by Y, in this order, and may further have the ninth nucleotide sequence portion and the eighth nucleotide sequence portion, in this order.

[0164] In another embodiment, the single-stranded oligonucleotide of the formula XLY comprises, in order, a seventh nucleotide sequence portion, an antisense sequence portion comprised by X, a first nucleotide sequence portion, L, a second nucleotide sequence portion, the ninth nucleotide sequence portion, the eighth nucleotide sequence portion, and an antisense sequence portion comprised by Y.

[0165] [B] When nucleotide sequence Y contains an antisense sequence It is preferable that Y has a second nucleotide sequence portion between the antisense sequence portion and L. The second nucleotide sequence portion and the antisense sequence portion may be directly bound to each other, or indirectly bound to each other via an oligonucleotide therebetween.

[0166] The antisense sequence is preferably a sequence that contains "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA" or a sequence that "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides", and the antisense sequence is more preferably a sequence that contains "at least four consecutive nucleotides recognized by RNase H when hybridized with the target RNA". The preferred form of the sequence is the same as that described above for the antisense sequence and the 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.

[0167] When the antisense sequence is a sequence containing "at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA," it is preferable that the second nucleotide sequence portion and the antisense sequence portion are indirectly linked via an oligonucleotide. The oligonucleotide is preferably one or more sugar-modified nucleotides that are adjacent to at least one of the 3' and 5' ends of the antisense sequence portion, and the embodiment is as described above.

[0168] 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 second nucleotide sequence portion and the antisense sequence portion may be directly linked or indirectly linked via an oligonucleotide between them, but direct linkage is preferred. When indirectly linked via an oligonucleotide, the oligonucleotide is the same as L' described below.

[0169] 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 in the specific cell to generate an oligonucleotide that is a part of the second oligonucleotide and contains the antisense sequence portion, and that it is easy to exert an antisense effect, it is preferable that the 5' side and 3' side of the second nucleotide sequence portion are linked to adjacent nucleotides by phosphodiester bonds.

[0170] Also, it is preferred that at least one sugar-modified nucleotide is bound adjacent to at least one of the 5' and 3' sides of the second nucleotide sequence portion. When Y is bound to L at the 5' side, it is more preferred that at least one sugar-modified nucleotide is bound adjacent to the 3' side of the second nucleotide sequence portion, and when Y is bound to L at the 3' side, it is more preferred that at least one sugar-modified nucleotide is bound adjacent to the 5' side of the second nucleotide sequence portion.

[0171] When the antisense sequence contains "at least four consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA," the sugar-modified nucleotide is preferably one or more sugar-modified nucleotides that are adjacently linked to either the 3' or 5' side of the antisense sequence, the embodiment of which is the same as described above. When the antisense sequence "contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides," the sugar-modified nucleotide is preferably a sugar-modified nucleotide on either the 3' or 5' side of the antisense sequence, the embodiment of which is the same as described above.

[0172] 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 contains 10 to 22 consecutive nucleotides, even more preferably contains 10 to 16 consecutive nucleotides, even more preferably contains 12 to 14 consecutive ribonucleotides, and particularly preferably contains 12 to 13 consecutive ribonucleotides.

[0173] As described above, the 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 the group derived from the second oligonucleotide is degraded by nucleases such as RNase H in a specific cell, so that an oligonucleotide containing the antisense sequence portion, which is at least a part of the second oligonucleotide, is generated and the antisense effect is easily exerted. In this respect, it is preferable that at least one of the 5' side and the 3' side of the first nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond. When X is linked to L at the 5' side, it is more preferable that the 3' side of the first nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond, and when X is linked to L at the 3' side, it is more preferable that the 5' side of the first nucleotide sequence portion is linked to the adjacent nucleotide by a phosphorothioate bond. In one embodiment, it is preferable that the nucleotides contained in the first oligonucleotide are linked to each other by phosphorothioate bonds.

[0174] From the viewpoint of suppressing degradation by enzymes such as RNase, it is preferable that 1 to 10 sugar-modified nucleotides are bound adjacent to at least one of the 5' and 3' sides of the first 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 first nucleotide sequence portion, and even more preferable that 2 or 3 sugar-modified nucleotides are bound adjacent to the 3' side of the first nucleotide sequence portion. 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 first nucleotide sequence portion, and even more preferable that 2 or 3 sugar-modified nucleotides are bound adjacent to the 5' side of the first nucleotide sequence portion. Here, a plurality of deoxyribonucleotides or ribonucleotides or both may be contained between the plurality of sugar-modified nucleotides at least one of the 3' and 5' sides, but it is preferable that the plurality of sugar-modified nucleotides are consecutive. When multiple sugar-modified nucleotides are bound adjacently to at least one of the 3' and 5' sides of the first nucleotide sequence portion, "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' sides of the first nucleotide sequence portion, each sugar-modified nucleotide may be the same or different.

[0175] 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.

[0176] The sugar-modified nucleotide moiety bound adjacent to at least one of the 3' and 5' sides of the first nucleotide sequence portion is the same as the sugar-modified nucleotide moiety bound adjacent to at least one of the 3' and 5' sides of the second nucleotide sequence described in detail in [A-1] above.

[0177] The embodiment of the first nucleotide sequence is 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 16 consecutive nucleotides, more preferably 8 to 12 consecutive nucleotides, and particularly preferably 9 to 11 consecutive deoxyribonucleotides.

[0178] In one embodiment, the number of nucleotides contained in X is preferably 7 to 50, more preferably 8 to 30, even more preferably 10 to 20, and particularly preferably 10 to 16. In this case, the number of nucleotides contained in X is smaller than the number of nucleotides contained in Y, and the difference is preferably 6 to 30, more preferably 8 to 25, even more preferably 10 to 20, and particularly preferably 13 to 15.

[0179] Nucleotide sequence X may further comprise a seventh nucleotide sequence comprising at least one ribonucleotide, which allows hybridization with the antisense sequence portion comprised by Y. In this case, in one embodiment, a single-stranded oligonucleotide represented by the formula XLY comprises, in this order, the seventh nucleotide sequence portion, the first nucleotide sequence portion, L, the second nucleotide sequence portion and the antisense sequence portion comprised by Y. The embodiment of the seventh nucleotide sequence is as described above in [A-1].

[0180] In this case, the number of nucleotides contained in X is preferably 10 to 50, more preferably 20 to 45, even more preferably 25 to 40, still more preferably 26 to 38, and particularly preferably 28 to 33. The difference between the number of nucleotides contained in Y and the number of nucleotides contained in X is preferably within 10, more preferably within 5, even more preferably within 4, even more preferably within 2, and particularly preferably 0.

[0181] Furthermore, the nucleotide sequence X may include an antisense sequence, and the embodiments in that case are as described in [A-1] and [A-2].

[0182] Furthermore, when the single-stranded oligonucleotide contains a partial structure of X'-L'-X, the fourth nucleotide sequence contained in the nucleotide sequence X' is the same as the fourth nucleotide sequence described in [A-1].

[0183] Next, L, L' and the functional molecule will be described. The following is common to several of the above-mentioned embodiments.

[0184] L is a group derived from an oligonucleotide that is degraded under physiological conditions, and is a linker that links the above-mentioned X and Y. L links the above-mentioned X and Y in the order of XLY.

[0185] L' is a group derived from an oligonucleotide that is degraded under physiological conditions, and is a linker that links the above-mentioned X and X'. L' links the above-mentioned X and X' in the order of X'-L'-X.

[0186] L and X are linked by a covalent bond, and for example, the sugar moieties of the terminal nucleotides of L and X (including a partial structure replacing the sugar backbone in a sugar-modified nucleotide) are preferably linked by a phosphodiester bond. L and Y are linked by a covalent bond, and for example, the sugar moieties of the terminal nucleotides of L and Y (including a partial structure replacing the sugar backbone in a sugar-modified nucleotide) are preferably linked by a phosphodiester bond. Similarly, the second nucleotide sequence portion in Y and L are preferably linked by a phosphodiester bond. Similarly, L' and X' are preferably linked by a phosphodiester bond, and L' and X are preferably linked by a phosphodiester bond.

[0187] Here, the "group derived from an oligonucleotide that is degraded under physiological conditions" may be any group derived from an oligonucleotide that is degraded by various enzymes such as DNase (deoxyribonuclease) and RNase (ribonuclease) under physiological conditions, and the nucleotides constituting the oligonucleotide may or may not be chemically modified in the base, sugar or phosphate bond in part or in whole.

[0188] It is desirable that L is degraded more quickly than the antisense sequence portion. L is preferably a group derived from an oligonucleotide linked by a phosphodiester bond, more preferably a group derived from an oligodeoxyribonucleotide or oligoribonucleotide, and even more preferably a group derived from DNA or RNA. L' is the same as L.

[0189] L may or may not contain a partially complementary sequence in the group derived from the oligonucleotide of L, but L is preferably a group derived from an oligonucleotide that does not contain a partially complementary sequence in the group derived from the oligonucleotide of L. An example of such a group derived from an oligonucleotide is (N)n (N is independently adenosine, uridine, cytidine, guanosine, 2'-deoxyadenosine, thymidine, 2'-deoxycytidine, or 2'-deoxyguanosine, and n is an integer (repetition number) of 1 to 40) linked by a phosphodiester bond. Among them, n is preferably 3 to 20, more preferably 4 to 10, even more preferably 4 to 7, even more preferably 4 or 5, and particularly preferably 4. The same applies to L'. In another embodiment of L', n is preferably 2 to 5, more preferably 2 to 4. L' may be the same sequence as L, or may be a different sequence.

[0190] The first oligonucleotide, the second oligonucleotide, the third oligonucleotide, the fourth oligonucleotide, or the fifth oligonucleotide may be directly or indirectly bound to a functional molecule. When the first oligonucleotide contains an antisense sequence portion, the functional molecule is preferably bound to the second oligonucleotide. The binding between the functional molecule and the second oligonucleotide may be direct or indirect via another substance, but it is preferable that the second oligonucleotide and the functional molecule are bound to each other by a covalent bond, an ionic bond, or a hydrogen bond. From the viewpoint of high stability of the binding, it is more preferable that they are bound directly by a covalent bond, or bound by a covalent bond via a linker (linking group). When the second oligonucleotide contains an antisense sequence portion, it is preferable that the functional molecule is bound to the first oligonucleotide. The binding between the functional molecule and the first oligonucleotide is the same as the binding between the functional molecule and the second oligonucleotide. When the first oligonucleotide and the second oligonucleotide each have an antisense sequence portion, and the second oligonucleotide contains the antisense sequence portion farthest from L, it is preferable that the functional molecule is bound to the first oligonucleotide, and when the first oligonucleotide contains the antisense sequence portion farthest from L, it is preferable that the functional molecule is bound to the second oligonucleotide. The binding between the functional molecule and the first or second oligonucleotide is the same as described above. When the fourth oligonucleotide has an antisense sequence portion, the functional molecule is preferably bound to the second oligonucleotide. The binding between the functional molecule and the second oligonucleotide is the same as described above.

[0191] When the functional molecule is covalently linked to the single-stranded oligonucleotide, the functional molecule is preferably directly or indirectly linked 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 by a phosphodiester bond or a modified phosphodiester bond, more preferably linked by a phosphodiester bond. In one embodiment, the terminal nucleotide of the second oligonucleotide and the linker or functional molecule are preferably linked by a phosphodiester bond or a modified phosphodiester bond, more preferably linked by a phosphodiester bond. In one embodiment, the terminal nucleotide of the first oligonucleotide and the linker or functional molecule are preferably linked by a phosphodiester bond or a modified phosphodiester bond, more preferably linked by a phosphodiester bond. The linker or functional molecule may be directly linked to the 3' oxygen atom of the 3' terminal nucleotide or the 5' oxygen atom of the 5' terminal nucleotide of the single-stranded oligonucleotide molecule.

[0192] The structure of the "functional molecule" is not particularly limited, and the binding of the functional molecule confers a desired function to the single-stranded oligonucleotide. The desired functions include a labeling function, a purification function, and a delivery function 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.

[0193] In addition, from the viewpoint of delivering a single-stranded oligonucleotide to a target site (e.g., a target cell) with high specificity and efficiency, and controlling the expression of a target gene very effectively by the single-stranded oligonucleotide, it is preferable that a molecule having a function of delivering the single-stranded oligonucleotide to a target site is bound as a functional molecule. For the molecule having the delivery function, for example, 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), etc. can be referred to.

[0194] As a molecule that imparts a delivery function to a target RNA, for example, from the viewpoint of being able to deliver a single-stranded oligonucleotide efficiently with high specificity to the liver, etc., lipids and sugars can be mentioned. Such lipids include cholesterol; fatty acids; fat-soluble vitamins such as vitamin E (tocopherols, 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, tocotrienols) are preferred from the viewpoint of higher safety. Among them, tocopherols are more preferred, tocopherol is even more preferred, and α-tocopherol is particularly preferred. As a sugar, a sugar derivative having an interaction with an asialoglycoprotein receptor can be mentioned.

[0195] The "asialoglycoprotein receptor" is present on the surface of liver cells, and recognizes the galactose residue of asialoglycoprotein, and takes up the molecule into the cell and degrades it. The "sugar derivative that interacts with the asialoglycoprotein receptor" is preferably a compound that has a structure similar to that of the galactose residue and is taken up into the cell by interacting with the asialoglycoprotein receptor, and examples of such a sugar derivative include GalNac (N-acetylgalactosamine) derivatives, galactose derivatives, and lactose derivatives. From the viewpoint of being able to deliver the single-stranded oligonucleotide of the present invention to the brain with high specificity and efficiency, the "functional molecule" includes sugars (e.g., glucose, sucrose, etc.). From the viewpoint of being able to deliver the single-stranded oligonucleotide to the organ with high specificity and efficiency by interacting with various proteins on the cell surface of each organ, the "functional molecule" includes receptor ligands, antibodies, and peptides or proteins of their fragments.

[0196] The linker that connects the functional molecule to the first oligonucleotide, the second oligonucleotide, the third oligonucleotide, the fourth oligonucleotide, or the fifth oligonucleotide is not particularly limited as long as it can exhibit the function of the functional molecule as a single-stranded oligonucleotide molecule, and can stably bind the functional molecule to the oligonucleotide. 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, and is preferably a C2-20 alkylene group or a C2-20 alkenylene group (the methylene groups contained in the alkylene group and the 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 the alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R Bis a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group. ), -S-, -S(O)- or -S(O)2- are replaced by. ). In this case, by combining the above substitutions and replacements, the linker is -C(O)-O-, -OC(O)-NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group), -C(O)-NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group), -C(S)-NR 1 -(R 1 represents a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group), -NR 1 -C(O)-NR 1 -(R 1 each independently represents a hydrogen atom, a C1-6 alkyl group or a halo C1-6 alkyl group), or the like.

[0197] The linker is more preferably a C2-20 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 a protected hydroxy group), still more preferably a C8-12 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), and particularly preferably a 1,8-octylene group. In another embodiment, the linker is particularly preferably a group represented by the following formula (III):

[0198] [ka]

[0199] 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).

[0200] In another embodiment, the linker is more preferably a C2-20 alkylene group, wherein each methylene group of the alkylene group is independently unsubstituted or -O- or -NR B -(R B is a hydrogen atom or a C1-6 alkyl group. Each unsubstituted methylene group is independently unsubstituted, or unsubstituted or substituted by an oxo group. ), more preferably a group represented by the formula -N(H)C(O)-(CH2) e -N(H)C(O)-(CH2) e A group represented by -C(O)- (wherein each e is independently an integer of 1 to 6), and a group represented by -N(H)C(O)-(CH2)2-N(H)C(O)-(CH2)2-C(O)- is particularly preferred.

[0201] The protecting group of the "protected hydroxyl group" is not particularly limited as long as it is stable when the functional molecule is bonded to the oligonucleotide. For example, any protecting group described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd Edition, John Wiley & Sons (1999) can be mentioned. Specific examples of such groups include a methyl group, a benzyl group, a p-methoxybenzyl group, a tert-butyl group, a methoxymethyl group, a methoxyethyl group, a 2-tetrahydropyranyl group, an ethoxyethyl group, a cyanoethyl group, a cyanoethoxymethyl group, a phenylcarbamoyl group, a 1,1-dioxothiomorpholine-4-thiocarbamoyl group, an acetyl group, a pivaloyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a [(triisopropylsilyl)oxy]methyl (Tom) group, a 1-(4-chlorophenyl)-4-ethoxypiperidin-4-yl (Cpep) group, a triphenylmethyl (trityl) group, a monomethoxytrityl group, a dimethoxytrityl (DMTr) group, a trimethoxytrityl group, a 9-phenylxanthen-9-yl (Pixyl) group, and a 9-(p-methoxyphenyl)xanthen-9-yl (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 tert-butyldimethylsilyl group, a triphenylmethyl(trityl) 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.

[0202] Preferred single-stranded oligonucleotides for use in nucleic acid drugs include those shown below. 1) Equation XLY (In the formula, X is a group derived from a first oligonucleotide consisting of 7 to 100 nucleotides which is independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and which contains 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; L is a group derived from a third oligonucleotide which is covalently bonded at both ends to the first oligonucleotide and the second oligonucleotide, respectively, and which is degraded under physiological conditions, the third oligonucleotide containing a phosphodiester bond; said first oligonucleotide having a nucleotide sequence X and said second oligonucleotide having a nucleotide sequence Y; said nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing with at least a portion of a second oligonucleotide and comprising at least four consecutive nucleotides recognized by RNase H; said 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 and the nucleotide sequence Y comprises at least one 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 a first nucleotide sequence portion and a second nucleotide sequence portion.

[0203] 2) The single-stranded oligonucleotide according to 1), wherein X is bound to L at the 3' side and Y is bound to L at the 5' side. 3) The single-stranded oligonucleotide according to 1), wherein X is bound to L at the 5' side and Y is bound to L at the 3' side.

[0204] 4) The single-stranded oligonucleotide according to any one of 1) to 3), wherein the complementarity between the antisense sequence and the sequence of a 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.

[0205] 6) The single-stranded oligonucleotide according to any one of 1) to 5), wherein the nucleotides contained in the single-stranded oligonucleotide represented by the formula XLY 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 each nucleotide contained in the single-stranded oligonucleotide represented by the formula XLY is linked to each other by at least one bond independently selected from a phosphodiester bond and a phosphorothioate bond.

[0206] 8) The single-stranded oligonucleotide according to any one of 1) to 8), wherein the nucleotides contained in the third oligonucleotide are linked to each other by phosphodiester bonds. 9) The single-stranded oligonucleotide according to any one of 1) to 8), wherein the third oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 10) The single-stranded oligonucleotide according to any one of 1) to 9), wherein the third oligonucleotide consists of 4 to 7 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 11) The single-stranded oligonucleotide according to any one of 1) to 10), wherein the third oligonucleotide is an oligodeoxyribonucleotide or an oligoribonucleotide. 12) The single-stranded oligonucleotide according to any one of 1) to 11), wherein the third oligonucleotide is DNA or RNA. 13) The single-stranded oligonucleotide according to any one of 1) to 12), wherein the third oligonucleotide is RNA.

[0207] 14) A single-stranded oligonucleotide according to any one of 1) to 13), 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. 15) The single-stranded oligonucleotide according to any one of 1) to 14), wherein the first oligonucleotide comprises a phosphorothioate bond. 16) The single-stranded oligonucleotide according to any one of 1) to 15), wherein the first nucleotide sequence is a sequence comprising nucleotides linked to each other by phosphorothioate bonds. 17) The single-stranded oligonucleotide according to any one of 1) to 16), wherein the first nucleotide sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide. 18) The single-stranded oligonucleotide according to any one of 1) to 17), wherein the first nucleotide sequence is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0208] 19) The single-stranded oligonucleotide according to any one of 1) to 18), wherein the second nucleotide sequence is a sequence comprising at least four consecutive nucleotides that are cleaved by RNase H. 20) The single-stranded oligonucleotide according to any one of 1) to 19), wherein the second nucleotide sequence is a sequence consisting of 4 to 25 ribonucleotides. 21) A single-stranded oligonucleotide according to any one of 1) to 20), 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. 22) The single-stranded oligonucleotide according to any one of 1) to 21), wherein the second oligonucleotide comprises a phosphodiester bond. 23) A single-stranded oligonucleotide according to any one of 1) to 22), in which 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. 24) The single-stranded oligonucleotide according to any one of 1) to 23), wherein the second nucleotide sequence is a sequence comprising nucleotides linked to each other by phosphodiester bonds.

[0209] 25) The single-stranded oligonucleotide according to any one of 1) to 24), wherein X comprises at least one sugar-modified nucleotide, and the nucleotide sequence X comprises at least one antisense sequence. 26) The single-stranded oligonucleotide according to 25), wherein the first nucleotide sequence is the antisense sequence. 27) The single-stranded oligonucleotide according to 25) or 26), wherein the first nucleotide sequence is a sequence containing at least 4 consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA. 28) A single-stranded oligonucleotide according to any one of 25) to 27), wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the first nucleotide sequence portion. 29) The single-stranded oligonucleotide according to any one of 25) to 28), wherein the nucleotides contained in the first oligonucleotide are linked to each other by phosphorothioate bonds. 30) The single-stranded oligonucleotide according to any one of 25) to 29), wherein the second nucleotide sequence is a sequence consisting of 4 to 20 ribonucleotides. 31) A single-stranded oligonucleotide according to any one of 25) to 30), in which 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.

[0210] 32) The single-stranded oligonucleotide according to 25), wherein X has the first nucleotide sequence portion between the antisense sequence portion and L. 33) The single-stranded oligonucleotide according to 32), wherein X comprises an oligonucleotide that is degraded under physiological conditions between the first nucleotide sequence portion and the antisense sequence portion. 34) The single-stranded oligonucleotide according to 33), wherein the oligonucleotide contained in X that is degraded under physiological conditions consists of 2 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 35) The single-stranded oligonucleotide according to 33) or 34), wherein the nucleotides contained in the oligonucleotide that is degraded under physiological conditions and that is contained in X are linked to each other via phosphodiester bonds. 36) The single-stranded oligonucleotide according to any one of 33) to 35), wherein the oligonucleotide contained in X that is degraded under physiological conditions is DNA or RNA consisting of 2 to 7 nucleotides.

[0211] 37) The single-stranded oligonucleotide according to any one of 32) to 36), wherein the antisense sequence portion contained in X contains a phosphorothioate bond. 38) The single-stranded oligonucleotide according to any one of 32) to 37), wherein the antisense sequence contained in the nucleotide sequence X is a sequence containing nucleotides linked to each other via phosphorothioate bonds.

[0212] 39) The single-stranded oligonucleotide according to any one of 32) to 38), wherein the first 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 X. 40) The single-stranded oligonucleotide according to any one of 32) to 39), wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the antisense sequence portion contained in the X. 41) The single-stranded oligonucleotide according to 39) or 40), wherein the sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' ends of the antisense sequence portion contained in the X is linked to at least one of the 5' and 3' ends of the antisense sequence portion contained in the X via a phosphorothioate bond.

[0213] 42) The single-stranded oligonucleotide according to any one of 32) to 41), wherein the antisense sequence contained in the nucleotide sequence X is a sequence consisting of 4 to 30 nucleotides independently selected from sugar-modified nucleotides and deoxyribonucleotides. 43) The single-stranded oligonucleotide according to any one of 32) to 42), wherein the antisense sequence contained in the nucleotide sequence X is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

[0214] 44) The single-stranded oligonucleotide according to any one of 32) to 43), wherein the antisense sequence contained in the nucleotide sequence X is a sequence containing at least 4 consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA. 45) The single-stranded oligonucleotide according to any one of 32) to 44), wherein the antisense sequence contained in the nucleotide sequence X is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0215] 46) The single-stranded oligonucleotide according to any one of 32) to 43), wherein the antisense sequence portion contained in X contains at least one sugar-modified nucleotide and does not contain an oligonucleotide strand consisting of four consecutive deoxyribonucleotides. 47) The single-stranded oligonucleotide according to 46), wherein at least one of the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in X is a sugar-modified nucleotide. 48) The single-stranded oligonucleotide according to 46) or 47), wherein the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in X are sugar-modified nucleotides. 49) The single-stranded oligonucleotide according to any one of 32) to 42), wherein the antisense sequence contained in the nucleotide sequence X is a sequence consisting of 4 to 30 sugar-modified nucleotides.

[0216] 50) The single-stranded oligonucleotide according to any one of 32) to 49), wherein the nucleotide sequence Y is capable of hybridizing with at least a portion of the antisense sequence portion contained in the X and comprises a sequence comprising at least 4 consecutive nucleotides that are cleaved by RNase H. 51) The single-stranded oligonucleotide according to 50), wherein the sequence containing at least 4 consecutive nucleotides that are cleaved by RNase H is a sequence consisting of 4 to 20 ribonucleotides. 52) A single-stranded oligonucleotide according to 50) or 51), wherein the second oligonucleotide comprises a sugar-modified nucleotide linked adjacent to at least one of the 5' and 3' sides of a sequence portion comprising at least four consecutive nucleotides that are cleaved by RNase H. 53) A single-stranded oligonucleotide according to any one of 50) to 52), in which at least one of the 5' and 3' ends of the sequence portion containing at least four consecutive nucleotides that are cleaved by RNase H is linked to the adjacent nucleotide via a phosphorothioate bond.

[0217] 54) A single-stranded oligonucleotide according to any one of 32) to 53), in which 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.

[0218] 55) The single-stranded oligonucleotide according to any one of 1) to 28) and 32) to 53), wherein the nucleotide sequence Y includes at least one antisense sequence. 56) The single-stranded oligonucleotide according to 55), wherein Y has the second nucleotide sequence portion between the antisense sequence portion and L.

[0219] 57) A single-stranded oligonucleotide according to 55) or 56), wherein the 5' and 3' ends of the second nucleotide sequence portion are linked to adjacent nucleotides via phosphodiester bonds.

[0220] 58) The single-stranded oligonucleotide according to any one of 55) to 57), wherein the antisense sequence portion contained in Y contains a phosphorothioate bond. 59) The single-stranded oligonucleotide according to any one of 55) to 58), wherein the antisense sequence contained in Y is a sequence containing nucleotides linked to each other by phosphorothioate bonds.

[0221] 60) The single-stranded oligonucleotide according to any one of 55) to 59), wherein the second 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 Y. 61) The single-stranded oligonucleotide according to any one of 55) to 60), wherein the second oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the antisense sequence portion contained in the Y. 62) The single-stranded oligonucleotide according to 60) or 61), wherein the sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' ends of the antisense sequence portion contained in the Y is linked to at least one of the 5' and 3' ends of the antisense sequence portion contained in the Y via a phosphorothioate bond.

[0222] 63) The single-stranded oligonucleotide according to any one of 55) to 62), wherein the antisense sequence contained in the nucleotide sequence Y is a sequence consisting of 4 to 30 nucleotides independently selected from sugar-modified nucleotides and deoxyribonucleotides. 64) The single-stranded oligonucleotide according to any one of 55) to 63), wherein the antisense sequence contained in Y is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

[0223] 65) A single-stranded oligonucleotide according to any one of 55) to 64), wherein the antisense sequence contained in the nucleotide sequence Y is a sequence containing at least four consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA. 66) The single-stranded oligonucleotide according to any one of 55) to 65), wherein the antisense sequence contained in Y is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0224] 67) A single-stranded oligonucleotide according to any one of 55) to 63), wherein the antisense sequence portion contained in Y contains at least one sugar-modified nucleotide and does not contain an oligonucleotide strand consisting of four consecutive deoxyribonucleotides. 68) The single-stranded oligonucleotide according to 67), wherein at least one of the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in Y is a sugar-modified nucleotide. 69) The single-stranded oligonucleotide according to 67) or 68), wherein the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in Y are sugar-modified nucleotides. 70) The single-stranded oligonucleotide according to any one of 55) to 63), wherein the antisense sequence contained in the nucleotide sequence Y is a sequence consisting of 4 to 30 sugar-modified nucleotides.

[0225] 71) The single-stranded oligonucleotide according to any one of 55) to 70), wherein the nucleotide sequence X is capable of hybridizing with at least a portion of the antisense sequence portion contained in the Y and comprises a sequence comprising at least 4 consecutive nucleotides that are cleaved by RNase H. 72) The single-stranded oligonucleotide according to 71), wherein the sequence containing at least 4 consecutive nucleotides that are cleaved by RNase H is a sequence consisting of 4 to 20 ribonucleotides. 73) A single-stranded oligonucleotide according to 71) or 72), wherein the first oligonucleotide comprises a sugar-modified nucleotide linked adjacent to at least one of the 5' and 3' sides of a sequence portion comprising at least four consecutive nucleotides that are cleaved by RNase H. 74) A single-stranded oligonucleotide according to any one of 71) to 73), in which at least one of the 5' and 3' ends of the sequence portion containing at least four consecutive nucleotides that are cleaved by RNase H is linked to the adjacent nucleotide via a phosphorothioate bond.

[0226] 75) formula X'-L'- (In the formula, X' is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides which is independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and which contains at least one nucleotide in which at least one of the sugar moiety, the base moiety, and the phosphate moiety has been modified; L' is a group derived from a fifth oligonucleotide which is covalently bonded to the first oligonucleotide and the fourth oligonucleotide at both ends thereof and which is degraded under physiological conditions; The fourth oligonucleotide has a nucleotide sequence X', and the nucleotide sequence X' comprises an antisense sequence that enables hybridization with a target RNA. The single-stranded oligonucleotide according to any one of 1) to 74), further comprising a group represented by: 76) The single-stranded oligonucleotide according to 75), wherein X' comprises the 5' end or the 3' end. 77) The single-stranded oligonucleotide according to 75) or 76), wherein the complementarity between the antisense sequence contained in the nucleotide sequence X' and the sequence of the target RNA is 70% or more. 78) The single-stranded oligonucleotide according to any one of 75) to 77), wherein the nucleotides contained in the single-stranded oligonucleotide represented by the formula X'-L'-XLY are each independently linked to each other by at least one bond 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. 79) A single-stranded oligonucleotide according to any one of 75) to 78), in which each nucleotide contained in the single-stranded oligonucleotide represented by the formula X'-L'-XLY is independently linked to each other by at least one bond selected from a phosphodiester bond and a phosphorothioate bond.

[0227] 80) The single-stranded oligonucleotide according to any one of 75) to 79), wherein the fifth oligonucleotide contains a phosphodiester bond. 81) A single-stranded oligonucleotide according to any one of 75) to 80), wherein the nucleotides contained in the fifth oligonucleotide are linked to each other by phosphodiester bonds. 82) A single-stranded oligonucleotide according to any one of 75) to 81), wherein the fifth oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. 83) The single-stranded oligonucleotide according to any one of 75) to 82), wherein the fifth oligonucleotide is an oligodeoxyribonucleotide or oligoribonucleotide consisting of 3 to 7 nucleotides. 84) A single-stranded oligonucleotide according to any one of 75) to 83), wherein the fifth oligonucleotide is an oligodeoxyribonucleotide or oligoribonucleotide consisting of 4 or 5 nucleotides. 85) A single-stranded oligonucleotide according to any one of 75) to 84), wherein the fifth oligonucleotide is DNA or RNA. 86) The single-stranded oligonucleotide according to any one of 75) to 85), wherein the fifth oligonucleotide is RNA.

[0228] 87) The single-stranded oligonucleotide according to any one of 75) to 86), wherein the fourth oligonucleotide comprises a phosphorothioate bond. 88) The single-stranded oligonucleotide according to any one of 75) to 87), wherein the antisense sequence contained in the nucleotide sequence X' is a sequence containing nucleotides linked to each other by phosphorothioate bonds. 89) A single-stranded oligonucleotide according to any one of 75) to 88), wherein the nucleotides contained in the fourth oligonucleotide are linked to each other by phosphorothioate bonds.

[0229] 90) The single-stranded oligonucleotide according to any one of 75) to 89), wherein the fourth oligonucleotide comprises a sugar-modified nucleotide linked adjacent to at least one of the 5' and 3' sides of the antisense sequence portion contained in X'. 91) The single-stranded oligonucleotide according to any one of 75) to 90), wherein the fourth oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the antisense sequence portion contained in X'.

[0230] 92) The single-stranded oligonucleotide according to any one of 75) to 91), wherein the antisense sequence contained in the nucleotide sequence X' is a sequence consisting of 4 to 30 nucleotides independently selected from sugar-modified nucleotides and deoxyribonucleotides. 93) The single-stranded oligonucleotide according to any one of 75) to 92), wherein the antisense sequence contained in the nucleotide sequence X' is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

[0231] 94) A single-stranded oligonucleotide according to any one of 75) to 93), wherein X' comprises at least one sugar-modified nucleotide, and the antisense sequence contained in the nucleotide sequence X' comprises at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA. 95) The single-stranded oligonucleotide according to any one of 75) to 94), wherein the antisense sequence contained in the nucleotide sequence X' is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0232] 96) The single-stranded oligonucleotide according to any one of 75) to 93), wherein the antisense sequence portion contained in X' contains at least one sugar-modified nucleotide and does not contain an oligonucleotide strand consisting of four consecutive deoxyribonucleotides. 97) The single-stranded oligonucleotide according to 96), wherein at least one of the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in X' is a sugar-modified nucleotide. 98) The single-stranded oligonucleotide according to 96) or 97), wherein the 3'-nucleotide and the 5'-nucleotide of the antisense sequence portion contained in X' are sugar-modified nucleotides. 99) The single-stranded oligonucleotide according to any one of 75) to 92), wherein the antisense sequence contained in the nucleotide sequence X' is a sequence consisting of 4 to 30 sugar-modified nucleotides.

[0233] 100) The single-stranded oligonucleotide according to any one of 75) to 99), wherein the nucleotide sequence Y is capable of hybridizing with at least a portion of the antisense sequence portion contained in X' and comprises a sequence comprising at least 4 consecutive nucleotides that are cleaved by RNase H. 101) The single-stranded oligonucleotide according to 100), wherein the sequence containing at least 4 consecutive nucleotides that are cleaved by RNase H is a sequence consisting of 4 to 20 ribonucleotides. 102) The single-stranded oligonucleotide according to 100) or 101), wherein the second oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5' and 3' sides of a sequence portion comprising at least four consecutive nucleotides that are cleaved by RNase H. 103) A single-stranded oligonucleotide according to any one of 100) to 102), in which at least one of the 5' and 3' ends of the sequence portion containing at least four consecutive nucleotides that are cleaved by RNase H is linked to adjacent nucleotides via phosphorothioate bonds.

[0234] 104) The single-stranded oligonucleotide according to any one of 1) to 74), wherein X comprises the 5' end or the 3' end. 105) The single-stranded oligonucleotide according to any one of 1) to 103), wherein Y comprises the 5' end or the 3' end. 106) A single-stranded oligonucleotide according to any one of 1) to 103), 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. 107) A single-stranded oligonucleotide according to any one of 1) to 103), wherein the group derived from the functional molecule is directly or indirectly bound to a second oligonucleotide. 108) A single-stranded oligonucleotide according to any one of 1) to 103), wherein the group derived from the functional molecule is directly or indirectly bound to the first oligonucleotide.

[0235] 109) The group derived from the functional molecule is a C2-20 alkylene group or a C2-20 alkenylene group (the methylene groups contained in the alkylene group and the 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 the alkenylene group are each independently unsubstituted or substituted with -O-, -NR B-(R B is a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group. ), -S-, -S(O)- or -S(O)2- are replaced by -S-, -S(O)- or -S(O)2-. The single-stranded oligonucleotide according to any one of 106) to 108), which is linked to the first oligonucleotide or the second oligonucleotide via a covalent bond or directly. 110) A single-stranded oligonucleotide according to any one of 106) to 109), in which the C2-20 alkylene group or C2-20 alkenylene group to which the group derived from the functional molecule is linked and the first oligonucleotide or the second oligonucleotide are linked via a phosphodiester bond or a modified phosphodiester bond. 111) A single-stranded oligonucleotide according to any one of 106) to 110), in which the C2-20 alkylene group or C2-20 alkenylene group to which the group derived from the functional molecule is linked and the first oligonucleotide or the second oligonucleotide are linked via a phosphodiester bond. 112) The single-stranded oligonucleotide according to any one of 106) to 111), wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides, proteins, and derivatives thereof. 113) The single-stranded oligonucleotide according to any one of 106) to 112), wherein the functional molecule is a lipid selected from the group consisting of cholesterol, a fatty acid, a fat-soluble vitamin, a glycolipid, and a glyceride. 114) The single-stranded oligonucleotide according to any one of 106) to 113), wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol, and tocotrienol. 115) The single-stranded oligonucleotide according to any one of 106) to 114), wherein the functional molecule is tocopherol and a hydroxy group of the tocopherol is bonded to the first oligonucleotide or the second oligonucleotide via 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). 116) The single-stranded oligonucleotide according to 115), wherein the hydroxy group of the tocopherol is linked to the first oligonucleotide or the second oligonucleotide via a 1,8-octylene group. 117) The single-stranded oligonucleotide according to any one of 106) to 112), wherein the functional molecule is a sugar derivative that interacts with an asialoglycoprotein receptor. 118) The single-stranded oligonucleotide according to any one of 106) to 112), wherein the functional molecule is a peptide or protein selected from the group consisting of a receptor ligand and an antibody.

[0236] 119) A single-stranded oligonucleotide according to any one of 1) to 118), 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. 120) A single-stranded oligonucleotide according to any one of 1) to 119), wherein the sugar-modified nucleotides are each independently a 2'-O-methylated nucleotide or LNA.

[0237] 121) A compound having a partial structure represented by the formula X'-L'-X-, the partial structure being represented by the formula X' 1 -X' 2 -X' 3 -L'-X 1 -X2 -X 3 - (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 an antisense sequence portion contained in X', 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 including at least one sugar-modified nucleotide, said oligonucleotide being covalently linked to a fifth oligonucleotide, L' is a group derived from an oligonucleotide consisting of 2 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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, the first nucleotide sequence being an antisense sequence and comprising at least 4 consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA; 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 a third oligonucleotide. 122) X' 1is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X' 3 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. 123) 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; 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. 124) X' 1 is a group derived from an oligonucleotide consisting of two or three LNAs, and X' 3 A single-stranded oligonucleotide according to any one of 121) to 123), wherein is a group derived from an oligonucleotide consisting of 2 or 3 nucleotides independently selected from LNA.

[0238] 125) Formula X' Z The partial structure includes a partial structure represented by the formula -L'-X-, X' Z -L'-X 1 -X 2 -X 3 - (In the formula, X' Z is an antisense sequence portion that contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides, and is covalently bound to a fifth oligonucleotide; L' is a group derived from an oligonucleotide consisting of 2 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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, the first nucleotide sequence being an antisense sequence and comprising at least 4 consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA; 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 a third oligonucleotide. 126) X' Z 125) The single-stranded oligonucleotide according to claim 125, wherein L is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides, and L' is a group derived from an oligonucleotide consisting of 2 to 5 nucleotides independently selected from deoxyribonucleotides. 127) X' Z is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides, LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides and 2'-O-methylcarbamoylethylated nucleotides. 128) X' ZThe single-stranded oligonucleotide according to 125) or 126), wherein is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides and LNAs.

[0239] 129) X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X 3 A single-stranded oligonucleotide according to any one of 121) to 128), wherein is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. 130) 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; 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. 131) X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 3 A single-stranded oligonucleotide according to any one of 121) to 130), wherein is a group derived from an oligonucleotide consisting of 2 or 3 nucleotides independently selected from LNA.

[0240] 132) The partial structure represented by the formula X- is X 4 -X 5 -X 1 -X 2 -X 3 - (In the formula, X 4 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 5 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, 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, the first nucleotide sequence being an antisense sequence and comprising at least 4 consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA; 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 a third oligonucleotide. 133) X 4 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, 5 is a group derived from an oligonucleotide consisting of 10 to 19 ribonucleotides, and X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X3 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. 134) X 4 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; 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; 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. 135) X 4 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs.

[0241] 136) The partial structure represented by the formula X- is X 1 -X 2 -X 3 - (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; X2 is a first nucleotide sequence portion, the first nucleotide sequence being an antisense sequence and comprising at least 4 consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA; 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 a third oligonucleotide. 137) X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, 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. 138) 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; 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. 139) X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs.

[0242] 140) The partial structure represented by the formula X- is X Z 1 -X Z 2 -X Z 3 -X 0 -X 2 - (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 X, 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; X 0 is a group derived from an oligonucleotide consisting of 2 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, X 2 is a first nucleotide sequence portion, which is covalently linked to a third oligonucleotide. 141) X Z 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, Z 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X Z 3 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides,2 is a group derived from an oligonucleotide consisting of 8 to 17 deoxyribonucleotides. 142) 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; X 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. 143) X Z 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X Z 3 is a group derived from an oligonucleotide consisting of two or three LNAs.

[0243] 144) The partial structure represented by formula X- is X Z -X 0 -X 2 - (In the formula, X Z is an antisense sequence portion which contains at least one sugar-modified nucleotide and does not contain an oligonucleotide strand consisting of four consecutive deoxyribonucleotides, X 0 is a group derived from an oligonucleotide consisting of 2 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, X 2is a first nucleotide sequence portion, which is covalently linked to a third oligonucleotide. 145) X Z is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides, 0 is a group derived from an oligonucleotide consisting of 2 to 5 nucleotides independently selected from deoxyribonucleotides, 2 is a group derived from an oligonucleotide consisting of 8 to 17 deoxyribonucleotides. 146) X Z is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides, LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides and 2'-O-methylcarbamoylethylated nucleotides. 147) X Z The single-stranded oligonucleotide according to 144) or 145), wherein is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides and LNAs.

[0244] 148) The partial structure represented by the formula X- is X 1 -X 2 - (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, which is covalently linked to a third oligonucleotide. 149) X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides, 2 is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides. 150) 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. 151) X 1 A single-stranded oligonucleotide according to any one of 148) to 150), wherein: is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0245] 152) The partial structure represented by formula -Y is -Y 2 -Y 1 (In the formula, Y 2 is a second nucleotide sequence portion, which is composed of 4 to 20 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and is derived from an oligonucleotide containing at least one ribonucleotide, and the oligonucleotide is covalently bonded to a third oligonucleotide, 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. 153) Y 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, and Y 1is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. 154) 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. 155) Y 1 A single-stranded oligonucleotide according to any one of 152) to 154), wherein: is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0246] 156) The partial structure represented by formula -Y is -Y 2 -Y 1 (In the formula, Y 2 is a group derived from an oligonucleotide comprising a second nucleotide sequence portion, consisting of 4 to 40 nucleotides independently selected from deoxyribonucleotides, ribonucleotides and sugar-modified nucleotides, and containing at least one ribonucleotide, the oligonucleotide being covalently bonded to a third oligonucleotide, 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. 157) Y 2 is a group derived from an oligonucleotide consisting of 25 to 36 ribonucleotides, and Y 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from sugar-modified nucleotides. 158) 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. 159) Y 1 A single-stranded oligonucleotide according to any one of 156) to 158), wherein: is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0247] 160) The partial structure represented by formula -Y is -Y 0 -Y Z 3 -Y Z 2 -Y Z 1 (In the formula, Y 0 is a second nucleotide sequence portion, covalently linked to the third oligonucleotide, 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; Y Z 2 is the antisense sequence portion contained in Y, 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. 161) Y 0 is a group derived from an oligonucleotide consisting of 10 to 22 ribonucleotides, and YZ 3 is 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. 162) Y Z 1 is a group derived from an oligonucleotide consisting of two or three 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 two or three nucleotides independently selected from LNA, 2'-O-methylated nucleotide, 2'-O-methoxyethylated nucleotide and 2'-O-methylcarbamoylethylated nucleotide. 163) 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.

[0248] 164) The partial structure represented by formula -Y is -Y 0 -Y Z (In the formula, Y 0 is a second nucleotide sequence portion, covalently linked to the third oligonucleotide, Y Zis an antisense sequence portion which contains at least one sugar-modified nucleotide and does not contain an oligonucleotide strand consisting of four consecutive deoxyribonucleotides. 165) Y 0 is a group derived from an oligonucleotide consisting of 10 to 22 ribonucleotides, and Y Z is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides and sugar-modified nucleotides. 166) Y Z is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides, LNA, 2'-O-methylated nucleotides, 2'-O-methoxyethylated nucleotides and 2'-O-methylcarbamoylethylated nucleotides. 167) Y Z The single-stranded oligonucleotide according to 164) or 165), wherein is a group derived from an oligonucleotide consisting of 6 to 30 nucleotides independently selected from deoxyribonucleotides and LNAs.

[0249] B-1) Formula XLY (In the formula, 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 containing at least one sugar-modified nucleotide, the first oligonucleotide has a first nucleotide sequence capable of hybridizing to a target RNA, the first nucleotide sequence being a sequence including at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA; Y is a group derived from a second oligonucleotide consisting of 4 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, the second oligonucleotide being capable of hybridizing with the first oligonucleotide and having a second nucleotide sequence containing at least one ribonucleotide; L is a group derived from a third oligonucleotide which is covalently bonded to the first oligonucleotide and the second oligonucleotide at both ends thereof and decomposed under physiological conditions, and the third oligonucleotide contains a phosphodiester bond; A single-stranded oligonucleotide in which X and Y hybridize intramolecularly at the first nucleotide sequence portion and the second nucleotide sequence portion. B-2) The single-stranded oligonucleotide according to B-1), in which X is bound to L at the 3' side and Y is bound to L at the 5' side. B-3) The single-stranded oligonucleotide according to B-1), in which X is bound to L at the 5' side and Y is bound to L at the 3' side. B-4) A single-stranded oligonucleotide according to any one of B-1) to B-3), in which the first nucleotide sequence has a complementarity of 70% or more with the sequence of the target RNA. B-5) A single-stranded oligonucleotide according to any one of B-1) to B-4), in which the complementarity between the first nucleotide sequence and the second nucleotide sequence is 70% or more.

[0250] B-6) A single-stranded oligonucleotide according to any one of B-1) to B-5), in which the nucleotides contained in the third oligonucleotide are linked to each other by phosphodiester bonds. B-7) A single-stranded oligonucleotide according to any one of B-1) to B-6), wherein the third oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. B-8) A single-stranded oligonucleotide according to any one of B-1) to B-7), wherein the third oligonucleotide is an oligodeoxyribonucleotide or an oligoribonucleotide. B-9) A single-stranded oligonucleotide according to any one of B-1) to B-8), wherein the third oligonucleotide is DNA or RNA. B-10) A single-stranded oligonucleotide according to any one of B-1) to B-9), wherein the third oligonucleotide is RNA. B-11) A single-stranded oligonucleotide according to any one of B-1) to B-10), wherein the third oligonucleotide is an oligonucleotide consisting of 4 or 5 adenosines.

[0251] B-12) A single-stranded oligonucleotide according to any one of B-1) to B-11), 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. B-13) A single-stranded oligonucleotide according to any one of B-1) to B-12), wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the first nucleotide sequence portion. B-14) A single-stranded oligonucleotide according to any one of B-1) to B-13), wherein the first oligonucleotide contains a phosphorothioate bond. B-15) A single-stranded oligonucleotide according to any one of B-1) to B-14), wherein the first nucleotide sequence is a sequence comprising nucleotides linked to each other by phosphorothioate bonds. B-16) A single-stranded oligonucleotide according to any one of B-1) to B-15), in which the nucleotides contained in the first oligonucleotide are linked to each other by phosphorothioate bonds. B-17) A single-stranded oligonucleotide according to any one of B-1) to B-16), wherein the first nucleotide sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide. B-18) A single-stranded oligonucleotide according to any one of B-1) to B-17), wherein the first nucleotide sequence is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0252] B-19) A single-stranded oligonucleotide according to any one of B-1) to B-18), wherein the second nucleotide sequence is a sequence containing at least four consecutive nucleotides that are cleaved by RNase H. B-20) A single-stranded oligonucleotide according to any one of B-1) to B-19), wherein the second nucleotide sequence is a sequence consisting of 4 to 20 ribonucleotides. B-21) A single-stranded oligonucleotide according to B-19) or B-20), in which 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. B-22) A single-stranded oligonucleotide according to any one of B-19) to B-21), 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. B-23) A single-stranded oligonucleotide according to any one of B-1) to B-22), in which Y includes the 5' end or the 3' end.

[0253] B-24) A single-stranded oligonucleotide according to any one of B-1) to B-22), 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. B-25) The single-stranded oligonucleotide according to B-24), in which the group derived from the functional molecule is directly or indirectly bound to a second oligonucleotide. B-26) The group derived from the functional molecule is a C2-20 alkylene group or a C2-20 alkenylene group (the methylene groups contained in the alkylene group and the 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 the alkenylene group are each independently unsubstituted or substituted with -O-, -NR B -(R Bis a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group. ), -S-, -S(O)- or -S(O)2- are replaced by. ), or directly covalently bonded to the second oligonucleotide. The single-stranded oligonucleotide according to B-24) or B-25). B-27) A single-stranded oligonucleotide according to any one of B-24) to B-26), wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides, proteins, and derivatives thereof. B-28) A single-stranded oligonucleotide according to any one of B-24) to B-27), wherein the functional molecule is a lipid selected from the group consisting of cholesterol, fatty acids, fat-soluble vitamins, glycolipids and glycerides. B-29) A single-stranded oligonucleotide according to any one of B-24) to B-28), wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol and tocotrienol. B-30) A single-stranded oligonucleotide according to any one of B-24) to B-29), wherein the functional molecule comprises tocopherol, and the hydroxyl group of the tocopherol is bound to the second oligonucleotide via 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 hydroxyl group). B-31) The functional molecule contains tocopherol, and the hydroxy group of the tocopherol is a 1,8-octylene group or a compound represented by the following formula (II): [ka] (wherein one * represents a bonding position to the second oligonucleotide, and the other * represents a bonding position to tocopherol). B-32) A single-stranded oligonucleotide according to any one of B-24) to B-27), wherein the functional molecule is a sugar derivative that interacts with an asialoglycoprotein receptor. B-33) A single-stranded oligonucleotide according to any one of B-24) to B-27), wherein the functional molecule is a peptide or protein selected from the group consisting of receptor ligands and antibodies.

[0254] B-34) A single-stranded oligonucleotide according to any one of B-1) to B-33), in which X includes the 5' end or the 3' end. B-35) formula X'-L'- (In the formula, X' is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and containing at least one sugar-modified nucleotide, the fourth oligonucleotide has a fourth nucleotide sequence that enables it to hybridize to the target RNA; the fourth nucleotide sequence is a sequence comprising at least four consecutive nucleotides that is recognized by RNase H when hybridized to the target RNA; L' is a group derived from the fifth oligonucleotide, which is covalently bound to the first oligonucleotide and the fourth oligonucleotide at both ends, respectively, and is degraded under physiological conditions. Here, the target RNA to which the first nucleotide sequence portion hybridizes and the target RNA to which the fourth nucleotide sequence portion hybridizes are the same or different. The single-stranded oligonucleotide according to any one of B-1) to B-33), further comprising a group represented by the following formula: B-36) The single-stranded oligonucleotide according to B-35), wherein X' comprises the 5' end or the 3' end. B-37) A single-stranded oligonucleotide according to B-35) or B-36), in which the fourth nucleotide sequence has a complementarity of 70% or more with the sequence of the target RNA.

[0255] B-38) A single-stranded oligonucleotide according to any one of B-35) to B-37), in which the nucleotides contained in the fifth oligonucleotide are linked to each other by phosphodiester bonds. B-39) A single-stranded oligonucleotide according to any one of B-35) to B-38), wherein the fifth oligonucleotide consists of 3 to 10 nucleotides independently selected from the group consisting of deoxyribonucleotides and ribonucleotides. B-40) A single-stranded oligonucleotide according to any one of B-35) to B-39), wherein the fifth oligonucleotide is DNA or RNA. B-41) A single-stranded oligonucleotide according to any one of B-35) to B-40), in which the fifth oligonucleotide is RNA consisting of 3 to 7 nucleotides.

[0256] B-42) A single-stranded oligonucleotide according to any one of B-35) to B-41), 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. B-43) A single-stranded oligonucleotide according to any one of B-35) to B-42), wherein the fourth oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5' and 3' sides of the fourth nucleotide sequence portion. B-44) A single-stranded oligonucleotide according to any one of B-35) to B-43), wherein the fourth oligonucleotide contains a phosphorothioate bond. B-45) A single-stranded oligonucleotide according to any one of B-35) to B-44), wherein the fourth nucleotide sequence is a sequence comprising nucleotides linked to each other by phosphorothioate bonds. B-46) A single-stranded oligonucleotide according to any one of B-35) to B-45), in which the nucleotides contained in the fourth oligonucleotide are linked to each other by phosphorothioate bonds. B-47) A single-stranded oligonucleotide according to any one of B-35) to B-46), wherein the fourth nucleotide sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide. B-48) A single-stranded oligonucleotide according to any one of B-35) to B-47), wherein the fourth nucleotide sequence is a sequence consisting of 4 to 20 deoxyribonucleotides.

[0257] B-49) A single-stranded oligonucleotide according to any one of B-1) to B-48), in which the sugar-modified nucleotides are each independently a 2'-O-methylated nucleotide, a 2'-O-methoxyethylated nucleotide, a 2'-O-aminopropylated nucleotide, a 2'-fluorinated nucleotide, a 2'-F-arabinonucleotide, a bridged nucleotide or a 2'-O-methylcarbamoylethylated nucleotide. B-50) A single-stranded oligonucleotide according to any one of B-1) to B-49), in which the sugar-modified nucleotides are each independently a 2'-O-methylated nucleotide or LNA. B-51) A single-stranded oligonucleotide according to any one of B-1) to B-50), in which the base moiety in the deoxyribonucleotide, ribonucleotide, or sugar-modified nucleotide is 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).

[0258] B-52) The partial structure represented by formula X- is X 1 -X 2 -X 3 - (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 group derived from the oligonucleotide of the first nucleotide sequence portion, 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 a third oligonucleotide. B-53) X 1 is a group derived from an oligonucleotide consisting of two or three sugar-modified nucleotides, 2 is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, and X 3 is a group derived from an oligonucleotide consisting of two or three sugar-modified nucleotides. B-54) 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; 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-55) X 1 is a group derived from an oligonucleotide consisting of two or three LNAs, X 3 is a group derived from an oligonucleotide consisting of two or three LNAs.

[0259] B-56) The partial structure represented by formula-Y is represented by the formula -Y 2 -Y1 (In the formula, Y 2 is a group derived from an oligonucleotide of a second nucleotide sequence portion, which is composed of 4 to 20 nucleotides independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides and contains at least one ribonucleotide, and the oligonucleotide is covalently bonded to a third oligonucleotide, 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-57) Y 2 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, and Y 1 is a group derived from an oligonucleotide consisting of two or three sugar-modified nucleotides. B-58) 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-59) Y 1 A single-stranded oligonucleotide according to any one of B-56) to B-58), wherein is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0260] B-60) formula X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a group derived from an oligonucleotide of the 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide of the 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, X 1 , X 2 , X 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds.

[0261] B-61) formula X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a group derived from an oligonucleotide of the 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide of the 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 a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule, X 1 , X 2 , X 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds. B-62) The single-stranded oligonucleotide according to B-61), wherein B is a C2-20 alkylene group (wherein the methylene groups of the alkylene group are each independently unsubstituted or replaced by -O-. The unsubstituted methylene groups are each independently unsubstituted or substituted by a hydroxy group), and A is a group derived from tocopherol. B-63) X 1 and X 2 , X 2 and X 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L and L and Y 2 A single-stranded oligonucleotide according to any one of B-60) to B-62), wherein each of the terminal nucleotides is linked by a phosphodiester bond.

[0262] B-64) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a group derived from an oligonucleotide of the 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 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2is a group derived from an oligonucleotide of a fourth 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide of the 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, X 1 , X 2 , X 3 , X' 1 , X' 2 , X' 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L, L' and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds.

[0263] B-65) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2is a group derived from an oligonucleotide of the 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 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2 is a group derived from an oligonucleotide of a fourth 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide of the 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 a C2-20 alkylene group or a C2-20 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 Bis a hydrogen atom, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule, X 1 , X 2 , X 3 , X' 1 , X' 2 , X' 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L, L' and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds. B-66) The single-stranded oligonucleotide according to B-65), wherein B is a C2-20 alkylene group (wherein the methylene groups of the alkylene group are each independently unsubstituted or replaced by -O-. The unsubstituted methylene groups are each independently unsubstituted or substituted by a hydroxy group), and A is a group derived from tocopherol. B-67) X 1 and X 2 , X 2 and X 3 , X' 1 and X' 2 , X' 2 and X' 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L, L and Y 2 , X' 3 and L' and L' and X 1 A single-stranded oligonucleotide according to any one of B-64) to B-66), wherein each of the terminal nucleotides is linked by a phosphodiester bond. B-68) X 1 and Y 1 A single-stranded oligonucleotide according to any one of B-60) to B-67), which hybridizes intramolecularly with B-69) X1 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of B-60) to B-68), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. B-70) X 3 and Y 2 A single-stranded oligonucleotide according to any one of B-60) to B-69), which hybridizes intramolecularly with B-71) X 2 -X 3 The nucleotide sequence of Y 2 The single-stranded oligonucleotide according to any one of B-60) to B-70), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0264] B-72) formula X' 1 -X' 2 -X' 3 -L' -X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a group derived from an oligonucleotide of the 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 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2 is a group derived from an oligonucleotide of a fourth 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide comprising a second nucleotide sequence portion, the group being derived from an oligonucleotide consisting of 25 to 36 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, X 1 , X 2 , X 3 , X' 1 , X' 2 , X' 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L, L' and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds.

[0265] B-73) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a group derived from an oligonucleotide of the 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 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2 is a group derived from an oligonucleotide of a fourth 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide comprising a second nucleotide sequence portion, the group being derived from an oligonucleotide consisting of 25 to 36 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule, X 1 , X 2 , X3 , X' 1 , X' 2 , X' 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L, L' and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds. B-74) The single-stranded oligonucleotide according to B-73), 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. B-75) X 1 and X 2 , X 2 and X 3 , X' 1 and X' 2 , X' 2 and X' 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L, L and Y 2 , X' 3 and L' and L' and X 1 A single-stranded oligonucleotide according to any one of B-72) to B-74), wherein each of the terminal nucleotides is linked by a phosphodiester bond. B-76) X' 1 and Y 1 A single-stranded oligonucleotide according to any one of B-72) to B-75), which hybridizes intramolecularly with B-77) X' 1 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of B-72) to B-76), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. B-78) X' 2 -X'3 -L'-X 1 and Y 2 A single-stranded oligonucleotide according to any one of B-72) to B-77), which hybridizes intramolecularly with B-79) X' 2 -X' 3 -L'-X 1 -X 2 -X 3 The nucleotide sequence of Y 2 The single-stranded oligonucleotide according to any one of B-72) to B-78), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0266] B-80) Y 2 A single-stranded oligonucleotide according to any one of B-56) to B-79), wherein is a group derived from RNA. B-81) Y 2 is a group derived from RNA consisting of 10 to 13 ribonucleotides. B-82) A single-stranded oligonucleotide according to any one of B-1) to B-81), wherein L is a group derived from DNA or RNA consisting of 4 to 7 nucleotides.

[0267] C-1) Formula X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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.

[0268] C-2) Formula X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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 a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule. C-3) The single-stranded oligonucleotide according to C-2), wherein B is a C2-20 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 hydroxyl 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) are linked via a phosphodiester bond.

[0269] C-5) X 1 , X 2 , X 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L and Y 2 The nucleotides contained in are linked to each other via phosphodiester bonds. C-6) X 1 and X 2 , X 2 and X 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X3 and L and L and Y 2 A single-stranded oligonucleotide according to any one of C-1) to C-5), wherein each of the terminal nucleotides is linked via a phosphodiester bond.

[0270] C-7) Formula X' Z -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of a 2'-O-methylated nucleotide and an LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 2 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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.

[0271] C-8) Formula X' Z -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of a 2'-O-methylated nucleotide and an LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 2 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule. C-9) B is a C2-20 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 hydroxyl group), and A is a group derived from tocopherol; the single-stranded oligonucleotide according to C-8). C-10) B is Y 1 and the terminal nucleotide of said single-stranded oligonucleotide according to C-8) or C-9) are linked via a phosphodiester bond.

[0272] 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, and L, L' and Y 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 2and X 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L, L and Y 2 , X' Z and L' and L' and X 1 The single-stranded oligonucleotide according to any one of C-7) to C-11), wherein each of the terminal nucleotides is linked via a phosphodiester bond.

[0273] C-13) X Z The single-stranded oligonucleotide according to any one of C-7) to C-12), which 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 3'- and 5'-nucleotides is independently selected from a 2'-O-methylated nucleotide and an LNA. C-15) X Z The single-stranded oligonucleotide according to C-13) or C-14), wherein the 3'- and 5'-nucleotides are independently selected from 2'-O-methylated nucleotides and LNA. C-16) X Z A single-stranded oligonucleotide according to any one of C-13) to C-15), in which is a group derived from an oligonucleotide consisting of nucleotides independently selected from 2'-O-methylated nucleotides and LNA.

[0274] C-17) X 1 and Y 1 and C-16) are hybridized intramolecularly. C-18) X 1 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of C-1) to C-17), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-19) X 3 and Y 2 and C-18) are hybridized intramolecularly. C-20) 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-1) to C-19), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0275] C-21) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2 is a fourth nucleotide sequence portion which is an antisense sequence portion contained in X', which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence containing at least 4 consecutive nucleotides which is recognized by RNase H when hybridized with a target RNA, and has a fourth nucleotide sequence which is an antisense sequence; X'3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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.

[0276] C-22) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2is a fourth nucleotide sequence portion which is an antisense sequence portion contained in X', which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence containing at least 4 consecutive nucleotides which is recognized by RNase H when hybridized with a target RNA, and has a fourth nucleotide sequence which is an antisense sequence; X' 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; 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 a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule. C-23) The single-stranded oligonucleotide according to C-22), 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 hydroxyl group), and A is a group derived from tocopherol. C-24) B is Y 1 and the terminal nucleotide of the single-stranded oligonucleotide according to C-22) or C-23) are linked via a phosphodiester bond.

[0277] C-25) X 1 , X 2 , X 3 , X' 1 , X' 2 , X' 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L, L' and Y 2 The single-stranded oligonucleotide according to any one of C-21) to C-24), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-26) X 1 and X 2 , X 2 and X 3 , X' 1 and X' 2 , X' 2 and X' 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L, L and Y 2 , X' 3 and L' and L' and X 1 The single-stranded oligonucleotide according to any one of C-21) to C-25), wherein each of the terminal nucleotides is linked via a phosphodiester bond. C-27) X 1 and Y 1 and C-26) are hybridized intramolecularly. C-28) X 1 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of C-21) to C-27), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-29) X 3 and Y 2 and C-28) are hybridized intramolecularly. C-30) 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-21) to C-29), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0278] C-31) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2is a fourth nucleotide sequence portion which is an antisense sequence portion contained in X', which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence containing at least 4 consecutive nucleotides which is recognized by RNase H when hybridized with a target RNA, and has a fourth nucleotide sequence which is an antisense sequence; X' 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide comprising a second nucleotide sequence portion and consisting of 25 to 36 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides.

[0279] C-32) formula X' 1 -X' 2 -X' 3 -L'-X 1 -X 2 -X 3 -LY 2 -Y 1 -BA (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X 2is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence including at least 4 consecutive nucleotides that is recognized by RNase H when hybridized with a target RNA, and has a first nucleotide sequence that is an antisense sequence; X 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, X' 2 is a fourth nucleotide sequence portion which is an antisense sequence portion contained in X', which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, which is a sequence containing at least 4 consecutive nucleotides which is recognized by RNase H when hybridized with a target RNA, and has a fourth nucleotide sequence which is an antisense sequence; X' 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; L' is a group derived from an oligonucleotide consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a group derived from an oligonucleotide comprising a second nucleotide sequence portion and consisting of 25 to 36 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule. C-33) The single-stranded oligonucleotide according to C-32), 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-34) B is Y 1 and the terminal nucleotide of said single-stranded oligonucleotide according to C-32) or C-33) are linked via a phosphodiester bond.

[0280] C-35) X 1 , X 2 , X 3 , X' 1 , X' 2 , X' 3 and Y 1 The nucleotides contained in are linked to each other by phosphorothioate bonds, and L, L' and Y 2 The single-stranded oligonucleotide according to any one of C-31) to C-34), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-36) X 1 and X 2 , X 2 and X 3 , X'1 and X' 2 , X' 2 and X' 3 and Y 2 and Y 1 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L, L and Y 2 , X' 3 and L' and L' and X 1 The single-stranded oligonucleotide according to any one of C-31) to C-35), wherein each of the terminal nucleotides is linked by a phosphodiester bond. C-37) X' 1 and Y 1 and C-36) are hybridized intramolecularly. C-38) X' 1 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of C-31) to C-37), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-39) Formula X' 2 -X' 3 -L'-X 1 -X 2 The partial structure represented by Y 2 and C-38) are hybridized intramolecularly. C-40) Formula X' 2 -X' 3 -L'-X 1 -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-31) to C-39), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0281] C-41) Y 2 is a group derived from RNA consisting of 10 to 13 ribonucleotides. C-42) Y 2 is a group derived from RNA consisting of 25 to 36 ribonucleotides.

[0282] C-43) formula X 1 -X 2 -LY 0 -Y Z (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 LNA, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 15 ribonucleotides, 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.

[0283] C-44) formula ABX 1 -X 2 -LY 0 -Y Z (In the formula, A is a group derived from a functional molecule, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by X 1 is a group derived from an oligonucleotide consisting of two or three nucleotides independently selected from 2'-O-methylated nucleotides and LNA, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 12 deoxyribonucleotides, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 10 to 15 ribonucleotides, 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-45) The single-stranded oligonucleotide according to C-44), 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-46) B is X 1 and the terminal nucleotide of said single-stranded oligonucleotide according to C-44) or C-45) are linked to each other via a phosphodiester bond.

[0284] C-47) X 1 , X 2 , Y Z The nucleotides contained in are linked to each other by phosphorothioate bonds, and L and Y 0 The single-stranded oligonucleotide according to any one of C-43) to C-46), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-48) X 1 and X 2 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 2 and L, L and Y 0 and Y 0 and Y Z The single-stranded oligonucleotide according to any one of C-43) to C-47), wherein each of the terminal nucleotides is linked by a phosphodiester bond. C-49) X 2 and Y 0 and C-48) are hybridized intramolecularly. C-50) 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-43) to C-49), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-51) Y 0is a group derived from RNA consisting of 10 to 15 ribonucleotides.

[0285] C-52) formula X 1 -X 2 -X 3 -LY 0 -Y Z (In the formula, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 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 2 or 3 LNAs, L is 4 to 7 independently selected from deoxyribonucleotides and ribonucleotides. A group derived from an oligonucleotide consisting of nucleotides, Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, 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.

[0286] C-53) A single-stranded oligonucleotide according to C-52), wherein the first nucleotide sequence is an antisense sequence and comprises at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA.

[0287] C-54) X 1 , X 2, X 3 and Y Z The nucleotides contained in are linked to each other by phosphorothioate bonds, and L and Y 0 The single-stranded oligonucleotide according to C-52) or C-53), wherein the nucleotides contained in are linked to each other via phosphodiester bonds. C-55) X 1 and X 2 and X 2 and X 3 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 3 and L, L and Y 0 and Y 0 and Y Z The single-stranded oligonucleotide according to any one of C-52) to C-54), wherein each of the terminal nucleotides is linked by a phosphodiester bond. C-56) X 2 and Y 0 and C-55) are hybridized intramolecularly. C-57) 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-52) to C-56), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-58) Y 0 is a group derived from RNA consisting of 12 to 16 ribonucleotides.

[0288] C-59) Formula-Y Z The partial structure represented by the formula -Y Z 3 -Y Z 2 -Y Z 1 It is expressed as Y Z 1is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, Y Z 2 is an antisense sequence portion contained in Y, which 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-60) Y Z A single-stranded oligonucleotide according to any one of C-43) to C-58), which does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. C-61) Y Z At least one of the 3'- and 5'-nucleotides is independently selected from 2'-O-methylated nucleotides and LNA. C-62) Y Z The single-stranded oligonucleotide according to C-60) or C-61), wherein the 3'- and 5'-nucleotides are independently selected from 2'-O-methylated nucleotides and LNA. C-63) Y Z is a group derived from an oligonucleotide consisting of a nucleotide independently selected from 2'-O-methylated nucleotides and LNA. R , C-60) to C-62) a single-stranded oligonucleotide.

[0289] C-64) formula X 4 -X 5 -X 1 -X 2 -X 3 -LY 0 -Y Z 3 -Y Z 2 -Y Z 1 (In the formula, X4 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, X 5 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, Y Z 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, Y Z 2 is an antisense sequence portion contained in Y, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, Y Z 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs. C-65) A single-stranded oligonucleotide according to C-64), wherein the first nucleotide sequence is an antisense sequence and comprises at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA.

[0290] C-66) formula ABX 4 -X 5 -X1 -X 2 -X 3 -LY 0 -Y Z 3 -Y Z 2 -Y Z 1 (In the formula, A is a group derived from a functional molecule, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by X 4 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, X 5 is a group derived from an oligonucleotide consisting of 10 to 13 ribonucleotides, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 0is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 12 to 16 ribonucleotides, Y Z 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, Y Z 2 is an antisense sequence portion contained in Y, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, Y Z 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs. C-67) A single-stranded oligonucleotide according to C-66), wherein the first nucleotide sequence is an antisense sequence and comprises at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA. C-68) The single-stranded oligonucleotide according to C-66) or C-67), 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-69) B is X 4 and the terminal nucleotide of said single-stranded oligonucleotide are linked via a phosphodiester bond.

[0291] C-70) X 4 , X 1 , X 2 , X 3 , Y Z 3 , Y Z 2 and Y Z 1 The nucleotides in X are linked to each other by phosphorothioate bonds. 5 , L and Y0 The single-stranded oligonucleotide according to any one of C-64) to C-69), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-71) X 4 and X 5 , X 1 and X 2 , X 2 and X 3 The terminal nucleotides of each are linked by phosphorothioate bonds, and X 5 and X 1 , X 3 and L, L and Y 0 and Y 0 and Y Z 3 The single-stranded oligonucleotide according to any one of C-64) to C-70), wherein each of the terminal nucleotides is linked by a phosphodiester bond. C-72) X 2 and Y 0 A single-stranded oligonucleotide according to any one of C-64) to C-71), which hybridizes intramolecularly with C-73) 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-64) to C-72), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-74) X 5 and Y Z 2 and C-73), which hybridize intramolecularly with each other. C-75) X 5 and the base sequence of the nucleotides constituting the formula Y Z 2 -Y Z 3 The single-stranded oligonucleotide according to any one of C-64) to C-74), having a complementarity of 70% or more with the base sequence of a nucleotide constituting a partial structure represented by the following formula: C-76) X4 and Y Z 1 and C-75) are hybridized intramolecularly. C-77) X 4 The nucleotide sequence of Y Z 1 The single-stranded oligonucleotide according to any one of C-64) to C-76), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0292] C-78) X 5 is a group derived from RNA consisting of 10 to 13 ribonucleotides. C-79) Y 0 is a group derived from RNA consisting of 12 to 16 ribonucleotides.

[0293] C-80) formula X 4 -X 5 -X 1 -X 2 -X 3 -LY 0 -Y Z 3 -Y Z 2 -Y Z 1 (In the formula, X 4 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, X 5 is a group derived from an oligonucleotide consisting of 12 to 19 ribonucleotides, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 14 to 22 ribonucleotides, Y Z 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, Y Z 2 is an antisense sequence portion contained in Y, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, Y Z 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs. C-81) A single-stranded oligonucleotide according to C-74), wherein the first nucleotide sequence is an antisense sequence and comprises at least four consecutive nucleotides that are recognized by RNase H when hybridized to the target RNA.

[0294] C-82) formula ABX 4 -X 5 -X 1 -X 2 -X 3 -LY 0 -Y Z 3 -Y Z 2 -Y Z 1 (In the formula, A is a group derived from a functional molecule, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by X 4 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, X 5 is a group derived from an oligonucleotide consisting of 12 to 19 ribonucleotides, X 1 is a group derived from an oligonucleotide consisting of 2 or 3 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 2 or 3 LNAs, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 0 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 14 to 22 ribonucleotides, Y Z 3 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs, Y Z 2 is an antisense sequence portion contained in Y, which is a group derived from an oligonucleotide consisting of 8 to 10 deoxyribonucleotides, Y Z 1 is a group derived from an oligonucleotide consisting of 2 or 3 LNAs. C-83) A single-stranded oligonucleotide according to C-82), wherein the first nucleotide sequence is an antisense sequence, the antisense sequence being a sequence comprising at least four consecutive nucleotides that are recognized by RNase H when hybridized to a target RNA. C-84) The single-stranded oligonucleotide according to C-82) or C-83), 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-85) B is X 4 and the terminal nucleotide of said single-stranded oligonucleotide are linked via a phosphodiester bond.

[0295] C-86) X 4 , X 1 , X 2 , X 3 , Y Z 3 , Y Z 2 and Y Z 1 The nucleotides in X are linked to each other by phosphorothioate bonds. 5 , L and Y 0 The single-stranded oligonucleotide according to any one of C-80) to C-85), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-87) X 4 and X 5 , X 1 and X 2 , X 2 and X 3 The terminal nucleotides of each are linked by phosphorothioate bonds, and X5 and X 1 , X 3 and L, L and Y 0 and Y 0 and Y Z 3 The single-stranded oligonucleotide according to any one of C-80) to C-86), wherein each of the terminal nucleotides is linked by a phosphodiester bond.

[0296] C-88) X 2 and Y 0 and C-87) are hybridized intramolecularly. C-89) 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-80) to C-88), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-90) X 5 and Y Z 2 and C-89) are hybridized intramolecularly. C-91) X 5 and the base sequence of the nucleotides constituting the formula Y Z 2 -Y Z 3 The single-stranded oligonucleotide according to any one of C-80) to C-90), having a complementarity of 70% or more with the base sequence of a nucleotide constituting a partial structure represented by the formula: C-92) X 5 A part of and Y 0 A single-stranded oligonucleotide according to any one of C-80) to C-91), which hybridizes intramolecularly with a portion of C-93) X 5 The nucleotide sequence constituting a part of Y 0A single-stranded oligonucleotide according to any one of C-80) to C-92), having a complementarity of 70% or more with a base sequence of a nucleotide constituting a part of said single-stranded oligonucleotide. C-94) X 4 and Y Z 1 and C-93), which hybridize intramolecularly with each other. C-95) X 4 The nucleotide sequence of Y Z 1 The single-stranded oligonucleotide according to any one of C-80) to C-94), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0297] C-96) X 5 is a group derived from RNA consisting of 12 to 19 ribonucleotides. C-97) Y 0 is a group derived from RNA consisting of 14 to 22 ribonucleotides.

[0298] C-98) formula X Z -X 0 -X 2 -LY 2 -Y 1 (In the formula, X Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of a 2'-O-methylated nucleotide and an LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; X 0 is a group derived from an oligonucleotide consisting of 2 to 5 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, X 2is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 17 deoxyribonucleotides, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 19 ribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides. C-99) formula X Z -X 0 -X 2 -LY 2 -Y 1 -BA (In the formula, X Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of a 2'-O-methylated nucleotide and an LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; X 0 is a group derived from an oligonucleotide consisting of 2 to 5 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, X 2 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 17 deoxyribonucleotides, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 2 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 8 to 19 ribonucleotides, Y 1is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule. C-100) The single-stranded oligonucleotide according to C-99), 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-101) B is Y 1 and the terminal nucleotide of said single-stranded oligonucleotide are linked via a phosphodiester bond.

[0299] C-102) X Z , X 2 and Y 1 The nucleotides in X are linked to each other by phosphorothioate bonds. 0 , L and Y 2 The single-stranded oligonucleotide according to any one of C-98) to C-101), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-103) Y 2 and Y 1The terminal nucleotides of each are linked by phosphorothioate bonds, and X Z and X 0 , X 0 and X 2 , X 2 and L and L and Y 2 The single-stranded oligonucleotide according to any one of C-98) to C-102), wherein each of the terminal nucleotides is linked by a phosphodiester bond. C-104) X 0 and Y 1 and C-103) are hybridized intramolecularly. C-105) X 0 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of C-98) to C-104), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-106) X 2 and Y 2 and C-105) are hybridized intramolecularly. C-107) X 2 The nucleotide sequence of Y 2 The single-stranded oligonucleotide according to any one of C-98) to C-106), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0300] C-108) X Z However, the single-stranded oligonucleotide according to any one of C-98) to C-107) does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. C-109) X Z The single-stranded oligonucleotide according to any one of C-98) to C-108), wherein at least one of the nucleotides at the 3' end and the 5' end is independently a nucleotide selected from a 2'-O-methylated nucleotide and an LNA. C-110) X ZThe single-stranded oligonucleotide according to any one of C-98) to C-109), wherein the 3'- and 5'-terminal nucleotides are independently selected from 2'-O-methylated nucleotides and LNA. C-111) Formula X Z - is a partial structure represented by the 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 2 or 3 LNAs, X Z 2 is an antisense sequence portion, which 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. C-112) X Z is a group derived from an oligonucleotide consisting of nucleotides independently selected from 2'-O-methylated nucleotides and LNA.

[0301] C-113) Y 2 is a group derived from RNA consisting of 8 to 19 ribonucleotides.

[0302] C-114) formula X Z -X 2 -X 3 -LY 3 -Y 2 -Y 1 (In the formula, X Zis a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of a 2'-O-methylated nucleotide and an LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; X 2 is a group derived from an oligonucleotide consisting of 4 to 8 nucleotides independently selected from ribonucleotides, X 3 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 4 to 8 deoxyribonucleotides, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 3 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 4 to 8 ribonucleotides, Y 2 is a group derived from an oligonucleotide consisting of 4 to 8 deoxyribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides. C-115) formula X Z -X 2 -X 3 -LY 3 -Y 2 -Y 1 -BA (In the formula, X Z is a group derived from an oligonucleotide containing an antisense sequence portion, having at least one of a 2'-O-methylated nucleotide and an LNA, and consisting of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA; X 2 is a group derived from an oligonucleotide consisting of 4 to 8 nucleotides independently selected from ribonucleotides, X 3 is a first nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 4 to 8 deoxyribonucleotides, L is a group derived from an oligonucleotide consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; Y 3 is a second nucleotide sequence portion, which is a group derived from an oligonucleotide consisting of 4 to 8 ribonucleotides, Y 2 is a group derived from an oligonucleotide consisting of 4 to 8 deoxyribonucleotides, Y 1 is a group derived from an oligonucleotide consisting of two or three 2'-O-methylated nucleotides, B is a C2-20 alkylene group or a C2-20 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, a C1-6 alkyl group or a haloC1-6 alkyl group; -S-, -S(O)- or -S(O)2- are replaced by A is a group derived from a functional molecule. C-116) The single-stranded oligonucleotide according to C-99), 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-117) B is Y 1and the terminal nucleotide of said single-stranded oligonucleotide according to C-115) or C-116) are linked via a phosphodiester bond.

[0303] C-118) X Z , X 3 , Y 2 and Y 1 The nucleotides in X are linked to each other by phosphorothioate bonds. 2 , L and Y 3 The single-stranded oligonucleotide according to any one of C-114) to C-117), wherein the nucleotides contained in are linked to each other by phosphodiester bonds. C-119) Y 3 and Y 2 , Y 2 and Y 1 and X 2 and X 3 The terminal nucleotides of each are linked by phosphorothioate bonds, and X Z and X 3 , X 3 and L and L and Y 3 The single-stranded oligonucleotide according to any one of C-114) to C-118), wherein each of the terminal nucleotides is linked by a phosphodiester bond. C-120) X 2 and Y 2 and hybridize intramolecularly to form X 3 and Y 3 and C-119) are hybridized intramolecularly. C-121) X 2 The nucleotide sequence that makes up Y 2 The complementarity with the base sequence of nucleotides constituting X is 70% or more, 3 The nucleotide sequence that makes up Y 3 The single-stranded oligonucleotide according to any one of C-114) to C-120), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more. C-122) X 2 and Y 1A single-stranded oligonucleotide according to any one of C-114) to C-121), which hybridizes intramolecularly with C-123) X 2 The nucleotide sequence of Y 1 The single-stranded oligonucleotide according to any one of C-114) to C-122), wherein the complementarity with the base sequence of the nucleotide constituting the single-stranded oligonucleotide is 70% or more.

[0304] C-124) X Z However, the single-stranded oligonucleotide according to any one of C-114) to C-123) does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides. C-125) X Z The single-stranded oligonucleotide according to any one of C-114) to C-124), wherein at least one of the 3'-terminus and 5'-terminus nucleotides is independently selected from 2'-O-methylated nucleotides and LNA. C-126) X Z The single-stranded oligonucleotide according to any one of C-114) to C-125, wherein the 3'- and 5'-terminal nucleotides are independently selected from 2'-O-methylated nucleotides and LNA. C-127) Formula X Z - is a partial structure represented by the 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 2 or 3 LNAs, X Z 2 is an antisense sequence portion, which 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. C-128) X Z is a group derived from an oligonucleotide consisting of a nucleotide independently selected from 2'-O-methylated nucleotides and LNA.

[0305] C-129) A single-stranded oligonucleotide according to any one of 1) to 167) and C-1) to C-128), in which the base moiety in the deoxyribonucleotide, ribonucleotide, or sugar-modified nucleotide is 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).

[0306] C-130) A single-stranded oligonucleotide according to any one of 1) to 167) and C-1) to C-129), wherein L is a group derived from DNA or RNA consisting of 4 to 7 nucleotides. C-131) A single-stranded oligonucleotide according to any one of 1) to 167) and C-1) to C-130), wherein the third oligonucleotide consists of 4 or 5 nucleotides independently selected from deoxyribonucleotides and ribonucleotides. C-132) A single-stranded oligonucleotide according to any one of 1) to 167) and C-1) to C-131), wherein the third oligonucleotide is an oligonucleotide consisting of adenosine.

[0307] D-1) A medicine comprising, as an active ingredient, a single-stranded oligonucleotide according to any one of 1) to 167) and C-1) to C-132). D-2) A medicine comprising, as an active ingredient, a single-stranded oligonucleotide according to any one of B-1) to B-82).

[0308] The single-stranded oligonucleotide according to B-60) or C-1) in which the first nucleotide sequence is an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 1. In the single-stranded oligonucleotide shown in Figure 1, X consisting of 2 or 3 LNAs is 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 10 to 13 ribonucleotides and having a second nucleotide sequence. 2 and Y consisting of two or three 2'-O-methylated nucleotides. 1 and are bonded in this order. X 1 From Y 1 The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 and a second nucleotide sequence Y 2 and form a double strand. X 1 and Y 1 Although X may or may not form a double strand, it is preferable that X forms a double strand. 3 and Y 2 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0309] The single-stranded oligonucleotide according to B-61) or C-2) in which the first nucleotide sequence is an antisense sequence and hybridizes intramolecularly with the first nucleotide sequence portion and the second nucleotide sequence portion is shown in Figure 2. In the single-stranded oligonucleotide shown in Figure 2, X consisting of 2 or 3 LNAs is 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 10 to 13 ribonucleotides and having a second nucleotide sequence. 2 and Y consisting of two or three 2'-O-methylated nucleotides. 1 X is bonded in this order to B, which is a C2-20 alkylene group, and A, which is a group derived from a functional molecule. 1 From Y 1 The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 and a second nucleotide sequence Y 2 and form a double strand. X 1 and Y 1 Although X may or may not form a double strand, it is preferable that X forms a double strand. 3 and Y 2 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0310] The single-stranded oligonucleotide according to B-64) or C-21) in which the first nucleotide sequence is an antisense sequence and hybridizes intramolecularly with the first nucleotide sequence portion and the second nucleotide sequence portion is shown in Figure 3. In the single-stranded oligonucleotide shown in Figure 3, X' consisting of 2 or 3 LNAs is 1 and X', which consists of 8 to 10 deoxyribonucleotides and has a fourth nucleotide sequence. 2 and X' consisting of two or three LNAs. 3 L' consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, and X consisting of 2 or 3 LNAs. 1 and X, which is a first nucleotide sequence consisting of 8 to 10 deoxynucleotides. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 10 to 13 ribonucleotides and having a second nucleotide sequence.2 and Y consisting of two or three 2'-O-methylated nucleotides. 1 and are bonded in this order. 1 From Y 1 The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 and a second nucleotide sequence Y 2 and form a double strand. X 1 and Y 1 Although X may or may not form a double strand, it is preferable that X forms a double strand. 3 and Y 2 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0311] A conceptual diagram of the single-stranded oligonucleotide according to B-65) or C-22) in which the first nucleotide sequence is an antisense sequence and hybridizes intramolecularly with the first nucleotide sequence portion and the second nucleotide sequence portion is shown in Figure 4. In the single-stranded oligonucleotide shown in Figure 4, X' consisting of 2 or 3 LNAs is 1 and X', which consists of 8 to 10 deoxyribonucleotides and has a fourth nucleotide sequence. 2 and X' consisting of two or three LNAs. 3 L' consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, and X consisting of 2 or 3 LNAs. 1 and X, which is a first nucleotide sequence consisting of 8 to 10 deoxynucleotides. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 10 to 13 ribonucleotides and having a second nucleotide sequence. 2 and Y consisting of two or three 2'-O-methylated nucleotides. 1 X' is bonded in this order to B, which is a C2-20 alkylene group or the like, and A, which is a group derived from a functional molecule. 1 From Y1 The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 and a second nucleotide sequence Y 2 and form a double strand. X 1 and Y 1 Although X may or may not form a double strand, it is preferable that X forms a double strand. 3 and Y 2 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0312] A conceptual diagram of the single-stranded oligonucleotide according to B-72) or C-31), in which the first nucleotide sequence is an antisense sequence, the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly, and the fourth nucleotide sequence portion and the sixth nucleotide sequence portion hybridize intramolecularly, is shown in Figure 5. In the single-stranded oligonucleotide shown in Figure 5, X' consisting of two or three LNAs is 1 and X', which consists of 8 to 10 deoxyribonucleotides and has a fourth nucleotide sequence. 2 and X' consisting of two or three LNAs. 3 L' consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, and X consisting of 2 or 3 LNAs. 1 and X, which is a first nucleotide sequence consisting of 8 to 10 deoxynucleotides. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 25 to 36 ribonucleotides and having a second nucleotide sequence and a sixth nucleotide sequence. 2 and Y consisting of two or three 2'-O-methylated nucleotides. 1 and are bonded in this order. 1 From Y 1 The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'.2 And, Y 2 and a portion having a fourth nucleotide sequence, X' 2 And, Y 2 The portion having the sixth nucleotide sequence X' forms a duplex. 1 and Y 1 Although X' may or may not form a double strand, it is preferable that X' forms a double strand. 3 , X 3 , L' and X 1 are each independently 2 The second nucleotide sequence and the sixth nucleotide sequence may or may not be duplexed, but preferably are duplexed. The second nucleotide sequence and the sixth nucleotide sequence may be the same or different.

[0313] A conceptual diagram of the single-stranded oligonucleotide according to B-73) or C-32), in which the first nucleotide sequence is an antisense sequence, the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly, and the fourth nucleotide sequence portion and the sixth nucleotide sequence portion hybridize intramolecularly, is shown in Figure 6. In the single-stranded oligonucleotide shown in Figure 6, X' consisting of 2 or 3 LNAs is 1 and X', which consists of 8 to 10 deoxyribonucleotides and has a fourth nucleotide sequence. 2 and X' consisting of two or three LNAs. 3 L' consisting of 3 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides, and X consisting of 2 or 3 LNAs. 1 and X, which is a first nucleotide sequence consisting of 8 to 10 deoxynucleotides. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 25 to 36 ribonucleotides and having a second nucleotide sequence and a sixth nucleotide sequence. 2 and Y consisting of two or three 2'-O-methylated nucleotides. 1X' is bonded in this order to B, which is a C2-20 alkylene group or the like, and A, which is a group derived from a functional molecule. 1 From Y 1 The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 And, Y 2 and a portion having a fourth nucleotide sequence, X' 2 And, Y 2 The portion having the sixth nucleotide sequence X' forms a duplex. 1 and Y 1 Although X' may or may not form a double strand, it is preferable that X' forms a double strand. 3 , X 3 , L' and X 1 are each independently 2 The second nucleotide sequence and the sixth nucleotide sequence may or may not be duplexed, but preferably are duplexed. The second nucleotide sequence and the sixth nucleotide sequence may be the same or different.

[0314] A schematic diagram of the single-stranded oligonucleotide according to C-43) in which nucleotide sequence Y contains an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 7. In the single-stranded oligonucleotide shown in Figure 7, X is composed of 2 or 3 2'-O-methylated nucleotides and a nucleotide selected from LNA. 1 and X, which is composed of 8 to 12 deoxyribonucleotides and has a first nucleotide sequence 2 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 10 to 15 ribonucleotides and having a second nucleotide sequence. 0 and Y having at least one of 2'-O-methylated nucleotides and LNA, which is composed of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, and has an antisense sequence. Z and are bonded in this order. X1 From Y Z The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 and a second nucleotide sequence Y 0 and form a double strand. X 1 and Y 0 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0315] A conceptual diagram of the single-stranded oligonucleotide according to C-44) in which the nucleotide sequence Y contains an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 8. In the single-stranded oligonucleotide shown in Figure 8, A is a group derived from a functional molecule, B is a C2-20 alkylene group or the like, and X is a nucleotide selected from 2 or 3 2'-O-methylated nucleotides and LNA. 1 and X, which is composed of 8 to 12 deoxyribonucleotides and has a first nucleotide sequence 2 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 10 to 15 ribonucleotides and having a second nucleotide sequence. 0 and Y having at least one of 2'-O-methylated nucleotides and LNA, which is composed of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides and LNA, and has an antisense sequence. Z and are bonded in this order. X 1 From Y Z The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 And, Y 0 The portion having the second nucleotide sequence of X forms a duplex. 1 and Y 0 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0316] A schematic diagram of the single-stranded oligonucleotide according to C-52) in which the nucleotide sequence Y comprises an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 9. The first nucleotide sequence may be an antisense sequence. In the single-stranded oligonucleotide shown in Figure 9, X, which is composed of 2 or 3 LNAs, 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 12 to 16 ribonucleotides and having a second nucleotide sequence. 0 and Y having at least one of 2'-O-methylated nucleotides and LNA, which is composed of 10 to 20 nucleotides independently selected from deoxyribonucleotides, 2'-O-methylated nucleotides, and LNA, and has an antisense sequence. Z and are bonded in this order. X 1 From Y Z The direction of binding to the first nucleotide sequence may be 5' to 3' or 3' to 5'. 2 and a second nucleotide sequence Y 0 and form a double strand. X 1 and X 3 are each independently 0 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0317] A schematic diagram of the single-stranded oligonucleotide according to C-64) in which nucleotide sequence Y contains an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 10. In the single-stranded oligonucleotide shown in Figure 10, X is composed of two or three 2'-O-methylated nucleotides. 4 and X, which consists of 10 to 13 ribonucleotides and has a seventh nucleotide sequence 5and X consisting of two or three LNAs 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 12 to 16 ribonucleotides and having a second nucleotide sequence. 0 and Y consisting of two or three LNAs. Z 3 and Y, which is composed of 8 to 10 deoxyribonucleotides and has an antisense sequence portion containing Y. Z 2 and Y consisting of two or three LNAs. Z 1 and are bonded in this order. X 4 From Y Z 1 The binding direction to the first nucleotide sequence may be from 5' to 3' or from 3' to 5'. The first nucleotide sequence may be an antisense sequence. 2 and a second nucleotide sequence Y 0 and Y form a duplex, and Y has an antisense sequence portion that Y contains Z 2 and a seventh nucleotide sequence, 5 and form a double strand. X 1 and X 3 are each independently 0 Although X may or may not form a double strand, it is preferable that X forms a double strand. 5 and Y Z 3 Although X may or may not form a double strand, it is preferable that X forms a double strand. 4 and Y Z 1 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0318] A conceptual diagram of the single-stranded oligonucleotide according to C-66) in which nucleotide sequence Y contains an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 11. The single-stranded oligonucleotide shown in Figure 11 has A, which is a group derived from a functional molecule, B, which is a C2-20 alkylene group or the like, and X, which is composed of two or three 2'-O-methylated nucleotides. 4 and X, which consists of 10 to 13 ribonucleotides and has a seventh nucleotide sequence 5 and X consisting of two or three LNAs 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 12 to 16 ribonucleotides and having a second nucleotide sequence. 0 and Y consisting of two or three LNAs. Z 3 and Y, which is composed of 8 to 10 deoxyribonucleotides and has an antisense sequence portion containing Y. Z 2 and Y consisting of two or three LNAs. Z 1 and are bonded in this order. A to Y Z 1 The binding direction to the first nucleotide sequence may be from 5' to 3' or from 3' to 5'. The first nucleotide sequence may be an antisense sequence. 2 and a second nucleotide sequence Y 0 and Y form a duplex, and Y has an antisense sequence portion that Y contains Z 2 and a seventh nucleotide sequence, 5 and form a double strand. X 1 and X 3 are each independently 0 Although X may or may not form a double strand, it is preferable that X forms a double strand. 5 and YZ 3 Although X may or may not form a double strand, it is preferable that X forms a double strand. 4 and Y Z 1 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0319] A schematic diagram of a single-stranded oligonucleotide according to C-80) in which nucleotide sequence Y contains an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 12. In the single-stranded oligonucleotide shown in Figure 12, X is composed of two or three 2'-O-methylated nucleotides. 4 and X, which consists of 11 to 19 ribonucleotides and has a seventh nucleotide sequence 5 and X consisting of two or three LNAs 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 14 to 22 ribonucleotides and having a second nucleotide sequence. 0 and Y consisting of two or three LNAs. Z 3 and Y, which is composed of 8 to 10 deoxyribonucleotides and has an antisense sequence portion containing Y. Z 2 and Y consisting of two or three LNAs. Z 1 and are bonded in this order. X 4 From Y Z 1 The binding direction to the first nucleotide sequence may be from 5' to 3' or from 3' to 5'. The first nucleotide sequence may be an antisense sequence. 2 And, Y 0 and a portion having a second nucleotide sequence of Y, which forms a duplex with Y having an antisense sequence portion comprising Y Z2 and a seventh nucleotide sequence, 5 and form a duplex, and Y 0 and X 5 and partially form a double strand. X 1 and X 3 are each independently 0 Although X may or may not form a double strand, it is preferable that X forms a double strand. 5 and Y Z 3 Although X may or may not form a double strand, it is preferable that X forms a double strand. 4 and Y Z 1 Although it may or may not form a double strand, it is preferable that it forms a double strand.

[0320] A conceptual diagram of the single-stranded oligonucleotide according to C-82) in which nucleotide sequence Y contains an antisense sequence and the first nucleotide sequence portion and the second nucleotide sequence portion hybridize intramolecularly is shown in Figure 13. The single-stranded oligonucleotide shown in Figure 13 comprises A, which is a group derived from a functional molecule, B, which is a C2-20 alkylene group or the like, and X, which is composed of two or three 2'-O-methylated nucleotides. 4 and X, which consists of 11 to 19 ribonucleotides and has a seventh nucleotide sequence 5 and X consisting of two or three LNAs 1 and X, which is composed of 8 to 10 deoxyribonucleotides and has a first nucleotide sequence. 2 and X consisting of two or three LNAs 3 L consisting of 4 to 7 nucleotides independently selected from deoxyribonucleotides and ribonucleotides; and Y consisting of 14 to 22 ribonucleotides an...

Claims

1. formula X-L-Y (wherein X is a group derived from a first oligonucleotide consisting of 7 to 100 nucleotides, which is independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and which contains 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; L is a group derived from a third oligonucleotide which is covalently bonded to the first oligonucleotide and the second oligonucleotide at both ends and which is degraded under physiological conditions; said first oligonucleotide having a nucleotide sequence X and said second oligonucleotide having a nucleotide sequence Y; the nucleotide sequence X comprises a first nucleotide sequence capable of hybridizing with at least a portion of a second oligonucleotide and comprising at least four consecutive nucleotides recognized by RNase H; said nucleotide sequence Y being capable of hybridizing to at least a portion of the first oligonucleotide and comprising a second nucleotide sequence comprising at least one ribonucleotide; said nucleotide sequence X comprises at least one antisense sequence capable of hybridizing with a target RNA; said X having said first nucleotide sequence portion between said antisense sequence portion and L; 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 a first nucleotide sequence portion and a second nucleotide sequence portion.

2. 2. The single-stranded oligonucleotide of claim 1, wherein X comprises at least one sugar-modified nucleotide.

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. 5. The single-stranded oligonucleotide of claim 1, wherein the nucleotides contained in the third oligonucleotide are linked to each other by phosphodiester bonds.

6. The single-stranded oligonucleotide of claim 1 , wherein the third oligonucleotide is DNA or RNA.

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

9. 9. The single-stranded oligonucleotide of claim 1, wherein the first oligonucleotide comprises a phosphorothioate bond.

10. 10. The single-stranded oligonucleotide according to any one of claims 1 to 9, wherein the first nucleotide sequence is a sequence of 4 to 20 nucleotides including at least one deoxyribonucleotide.

11. 11. 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.

12. The single-stranded oligonucleotide of claim 11, 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.

13. 13. The single-stranded oligonucleotide according to claim 11 or 12, 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.

14. The single-stranded oligonucleotide according to any one of claims 1 to 13, wherein the first oligonucleotide comprises a sugar-modified nucleotide bound adjacent to at least one of the 5'-side and the 3'-side of the antisense sequence portion comprised by said X.

15. The single-stranded oligonucleotide according to any one of claims 1 to 13, wherein the first oligonucleotide comprises sugar-modified nucleotides bound adjacent to the 5'-side and 3'-side of the antisense sequence portion comprised by said X.

16. The single-stranded oligonucleotide according to any one of claims 1 to 15, wherein the antisense sequence contained in the nucleotide sequence X is a sequence containing at least 4 consecutive nucleotides that are recognized by RNase H when hybridized with a target RNA.

17. The single-stranded oligonucleotide according to any one of claims 1 to 16, wherein the antisense sequence portion contained in X contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides.

18. 18. The single stranded oligonucleotide of any one of claims 1 to 17, wherein X comprises the 5' end or the 3' end.

19. formula X'-L'- (wherein X' is a group derived from a fourth oligonucleotide consisting of 7 to 100 nucleotides, which is independently selected from deoxyribonucleotides, ribonucleotides, and sugar-modified nucleotides, and which contains at least one nucleotide modified in at least one of the sugar moiety, the base moiety, and the phosphate moiety; L' is a group derived from the fifth oligonucleotide which is covalently bonded to the first oligonucleotide and the fourth oligonucleotide at both ends thereof and which is degraded under physiological conditions; The fourth oligonucleotide has an antisense sequence that enables it to hybridize with a target RNA. The single-stranded oligonucleotide according to any one of claims 1 to 17, further comprising a group represented by:

20. X' comprises at least one sugar-modified nucleotide; The single-stranded oligonucleotide of claim 19, wherein the antisense sequence of the fourth oligonucleotide is a sequence containing at least four consecutive nucleotides that is recognized by RNase H when hybridized to a target RNA.

21. The single-stranded oligonucleotide according to claim 19, wherein the antisense sequence portion of the fourth oligonucleotide contains at least one sugar-modified nucleotide and does not contain an oligonucleotide chain consisting of four consecutive deoxyribonucleotides.

22. The single-stranded oligonucleotide according to claim 20 or 21, wherein the antisense sequence portion of the fourth oligonucleotide hybridizes to at least a portion of the second oligonucleotide.

23. 23. The single-stranded oligonucleotide of any one of claims 19 to 22, wherein the nucleotides contained in the fifth oligonucleotide are linked to each other by phosphodiester bonds.

24. 24. The single-stranded oligonucleotide of any one of claims 19 to 23, wherein the fifth oligonucleotide is DNA or RNA.

25. 25. The single-stranded oligonucleotide according to any one of claims 1 to 24, comprising a sugar-modified nucleotide linked adjacent to at least one of the 5' and 3' ends of the antisense sequence portion.

26. 26. The single-stranded oligonucleotide according to any one of claims 1 to 25, comprising sugar-modified nucleotides linked adjacent to the 5' and 3' ends of the antisense sequence portion.

27. 27. The single-stranded oligonucleotide according to any one of claims 1 to 26, wherein the antisense sequence is a sequence consisting of 4 to 20 nucleotides including at least one deoxyribonucleotide.

28. 28. The single-stranded oligonucleotide of any one of claims 1 to 27, wherein the antisense sequence portion comprises a phosphorothioate bond.

29. The single-stranded oligonucleotide according to any one of claims 1 to 28, 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.

30. 30. The single stranded oligonucleotide of any one of claims 1 to 29, wherein Y comprises the 5' end or the 3' end.

31. The single-stranded oligonucleotide according to any one of claims 1 to 30, 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.

32. 32. The single-stranded oligonucleotide of claim 31, wherein the functional molecule is selected from the group consisting of sugars, lipids, peptides and proteins, and derivatives thereof.

33. 33. The single-stranded oligonucleotide of claim 31 or 32, wherein the functional molecule is a lipid selected from the group consisting of cholesterol, tocopherol, and tocotrienol.

34. 33. The single-stranded oligonucleotide of claim 31 or 32, wherein the functional molecule is a sugar derivative that interacts with the asialoglycoprotein receptor.

35. 33. The single-stranded oligonucleotide of claim 31 or 32, wherein the functional molecule is a peptide or protein selected from the group consisting of a receptor ligand and an antibody.

36. 36. A pharmaceutical composition comprising the single-stranded oligonucleotide of any one of claims 1 to 35 and a pharmacologically acceptable carrier.

37. A method for regulating the function of a target RNA, comprising the step of contacting a cell (excluding a human cell) with a single-stranded oligonucleotide described in any one of claims 1 to 35.

38. 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 35.

39. 40. Use of a single-stranded oligonucleotide according to any one of claims 1 to 35 for controlling the function of a target RNA in a mammal (excluding humans).

40. 36. A method for producing a single-stranded oligonucleotide according to any one of claims 1 to 35, comprising extending a nucleotide chain at the 3'-end or 5'-end of an oligonucleotide comprising at least one of X, L and Y.

Images