WO2023138663A1 - Arn double brin, son utilisation et son procédé de préparation - Google Patents

Arn double brin, son utilisation et son procédé de préparation Download PDF

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WO2023138663A1
WO2023138663A1 PCT/CN2023/073189 CN2023073189W WO2023138663A1 WO 2023138663 A1 WO2023138663 A1 WO 2023138663A1 CN 2023073189 W CN2023073189 W CN 2023073189W WO 2023138663 A1 WO2023138663 A1 WO 2023138663A1
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nucleotide
seq
dsrna
antisense strand
nucleotides
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PCT/CN2023/073189
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English (en)
Chinese (zh)
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李云飞
林晓燕
张瑱
王艳辉
董玉琼
茅松
周雅琴
黄龙飞
黄燕芬
黄敏印
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上海拓界生物医药科技有限公司
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Publication of WO2023138663A1 publication Critical patent/WO2023138663A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing

Definitions

  • the present disclosure relates to a technical field of using dsRNA to reduce the expression of target RNA and to treat related diseases, in particular, the present disclosure relates to the preparation and application of dsRNA.
  • AGT is also known as SERPINA8 or ANHU.
  • AGT encoded by the AGT gene, is mainly produced by the liver and is a rate-limiting substrate of the renin-angiotensin system (RAS) and a precursor of the angiotensin peptide.
  • RAS renin-angiotensin system
  • AGT is cleaved to angiotensin I, which is subsequently converted to angiotensin II by the action of circulating and locally expressed angiotensin-converting enzyme (ACE).
  • ACE angiotensin-converting enzyme
  • Angiotensin II is the most important biologically active substance in the renin-angiotensin-aldosterone system (RAAS).
  • angiotensin II type 1 receptor
  • AT1R angiotensin II type 1 receptor
  • ER essential hypertension
  • Hypertension is a common cardiovascular disease worldwide, with a global prevalence as high as 10% to 20%. It can lead to cerebrovascular, cardiac and renal complications, and is a major risk factor for various diseases, disorders and conditions (such as stroke, coronary heart disease, chronic kidney disease, myocardial infarction, heart failure, aneurysm, peripheral arterial disease, heart injury and other cardiovascular-related diseases).
  • diseases, disorders and conditions such as stroke, coronary heart disease, chronic kidney disease, myocardial infarction, heart failure, aneurysm, peripheral arterial disease, heart injury and other cardiovascular-related diseases.
  • drugs for the treatment of hypertension including diuretics, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers.
  • RNA interference is an effective way to silence gene expression. According to statistics, more than 80% of the disease-related proteins in the human body cannot be targeted by current conventional small molecule drugs and biological macromolecular preparations, and are non-druggable proteins. Using RNA interference technology, it is possible to design appropriate dsRNA based on the mRNA encoding these proteins, specifically target the target mRNA and degrade the target mRNA, thereby inhibiting the production of related proteins. Therefore, dsRNA has very important prospects for drug development. However, in order to achieve the RNA interference effect for therapeutic purposes in vivo, it is necessary to deliver dsRNA molecules to specific cells in vivo.
  • Conjugate dsRNA with a targeting ligand and use the molecular structure of the targeting ligand and the receptor on the surface of the cell membrane, from Endocytosis into cells is an effective drug delivery method.
  • asialoglycoprotein receptor (ASGPR) is a receptor specifically expressed in hepatocytes, which has high abundance on the surface of hepatocytes and is characterized by rapid intracellular and extracellular transitions.
  • Monosaccharide and polysaccharide molecules such as galactose, galactosamine, and N-acetylgalactosamine have high affinity for ASGPR.
  • the present disclosure provides a double-stranded ribonucleic acid (dsRNA), which comprises a sense strand and an antisense strand, wherein the sense strand and the antisense strand comprise continuous nucleotides according to the direction from the 5' end to the 3' end, wherein the nucleotides at positions 7, 8, and 9 of the sense strand are 2'-fluoro-modified nucleotides, the 5th nucleotides are independently 2'-methoxy-modified nucleotides or 2'-fluoro-modified nucleotides, and the nucleotides at the remaining positions are 2'-methoxy-modified nucleotides;
  • the nucleotides at position 14 are 2'-fluoro-modified nucleotides, the nucleotides at positions 4, 6, 8, 9, 10, 12, 16 and 18 are independently 2'-methoxy or 2'-fluoro-modified nucleotides, and the nucleotides at
  • At least one nucleotide position from the 2nd to the 8th position of the antisense strand contains a chemical modification represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof:
  • Y is selected from O, NH and S;
  • Each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • J 2 is H or C 1 -C 6 alkyl
  • Q 1 is Q 2 is R 2 ; or Q 1 is R 2 and Q 2 is
  • J 1 is H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a ring
  • B is a base
  • the chemical modification represented by formula (I), its tautomer, or a pharmaceutically acceptable salt thereof is replaced with a 2'-methoxy modification.
  • At least one nucleotide in the 2nd to 8th positions of the antisense strand is a 2'-methoxy-modified nucleotide.
  • the 2'-fluoro-modified nucleotides at positions 2, 4, 6, 10, 12, 14 and 16 of the 5' end of the antisense strand.
  • the 2'-fluoro-modified nucleotides at positions 2, 4, 6, 10, 14 and 16 of the 5' end of the antisense strand are identical to each other.
  • the 2'-fluoro-modified nucleotides at positions 2, 4, 6, 12, 14 and 16 of the 5' end of the antisense strand are identical to each other.
  • the 2'-fluoro-modified nucleotides at positions 2, 6, 10, 12, 14 and 16 of the 5' end of the antisense strand are identical to each other.
  • positions 2, 6, 14 and 16 at the 5' end of the antisense strand are 2'-fluoro-modified nucleotides.
  • the 2'-fluoro-modified nucleotides at positions 2, 4, 6, 14 and 16 at the 5' end of the antisense strand are identical to each other.
  • the 2'-fluoro-modified nucleotides at positions 2, 6, 10, 14 and 16 at the 5' end of the antisense strand are identical to each other.
  • positions 2, 6, 12, 14 and 16 at the 5' end of the antisense strand are 2'-fluoro-modified nucleotides.
  • the 6th, 14th and 16th positions at the 5' end of the antisense strand are 2'-fluoro modified of nucleotides.
  • the 2'-fluoro-modified nucleotides at positions 2, 14 and 16 at the 5' end of the antisense strand are identical to each other.
  • positions 2, 6 and 14 at the 5' end of the antisense strand are 2'-fluoro-modified nucleotides.
  • the chemical modification shown in formula (I) is selected from the chemical modification shown in formula (I-1):
  • Y is selected from O, NH and S;
  • Each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • Each J 1 and J 2 are independently H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5 modified pyrimidine, Thymine, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification shown in formula (I) is selected from the chemical modification shown in formula (I-2):
  • Y is selected from O, NH and S;
  • Each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • Each J 1 and J 2 are independently H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are each independently H, methyl, ethyl, n-propyl or isopropyl;
  • Each J 1 and J 2 are independently H or methyl
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are each independently H, methyl, ethyl, n-propyl or isopropyl;
  • Each J 1 and J 2 are independently H or methyl
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • J 1 and J 2 are independently H;
  • R 1 is selected from H, methyl and CH 2 OH;
  • R 2 is selected from H, OH, NH 2 , methyl and CH 2 OH;
  • R 3 is selected from H, OH, NH 2 , methyl and CH 2 OH;
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5 modified pyrimidine, Thymine, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • J 1 and J 2 are independently H;
  • R 1 is selected from H, methyl and CH 2 OH;
  • R 2 is selected from H, methyl and CH 2 OH;
  • R 3 is selected from H, OH, NH 2 , methyl and CH 2 OH;
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Y is O or NH
  • Each X is independently selected from CR 4 (R 4 '), NR 5 and NH-CO, R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • J 2 is H or C 1 -C 6 alkyl
  • R 3 is selected from H, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and (CH 2 ) p R 6 ;
  • Q 1 is Q 2 is R 2 ; or Q 1 is R 2 and Q 2 is
  • R 1 is selected from H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and (CH 2 ) q R 7 ;
  • J 1 is H or C 1 -C 6 alkyl
  • R 2 is selected from H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and (CH 2 ) r R 8 ;
  • R 1 and R 2 are directly connected to form a 3-6 membered ring;
  • B is a base
  • X is independently selected from CR 4 (R 4 ′) and NH—CO.
  • X is independently selected from CR 4 (R 4 ′).
  • R 3 is selected from H, C 1 -C 6 alkyl, and (CH 2 ) p R 6 .
  • R 3 is selected from H and C 1 -C 6 alkyl.
  • R 1 is selected from H, C 1 -C 6 alkyl, and (CH 2 ) q R 7 .
  • R 1 is selected from H and C 1 -C 6 alkyl.
  • R 2 is selected from H, OH, C 1 -C 6 alkyl, and (CH 2 ) r R 8 .
  • R 2 is selected from H, C 1 -C 6 alkyl, and (CH 2 ) r R 8 .
  • Y is O
  • Each X is independently selected from CR 4 (R 4 ') and NH-CO, R 4 and R 4 ' are independently H or C 1 -C 6 alkyl;
  • J 2 is H or C 1 -C 6 alkyl
  • R 3 is selected from H, C 1 -C 6 alkyl and (CH 2 ) p R 6 ;
  • Q 1 is Q 2 is R 2 ; or Q 1 is R 2 and Q 2 is
  • R 1 is selected from H, C 1 -C 6 alkyl and (CH 2 ) q R 7 ;
  • J 1 is H or C 1 -C 6 alkyl
  • R 2 is selected from H, OH, C 1 -C 6 alkyl and (CH 2 ) r R 8 ;
  • R 1 and R 2 are directly connected to form a 5-6 membered ring;
  • B is a base
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitro pyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Y is O
  • Each X is independently selected from CR 4 (R 4 '), R 4 and R 4 ' are independently H or C 1 -C 6 alkyl;
  • R 3 is selected from H and C 1 -C 6 alkyl
  • Q 1 is Q 2 is R 2 ; or Q 1 is R 2 and Q 2 is
  • R 1 is selected from H and C 1 -C 6 alkyl
  • J 1 is H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a 5-6 membered ring;
  • B is a base
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Y is O.
  • X is independently selected from CR 4 (R 4 '), NR 5 and NH-CO, R 4 , R 4 ', R 5 are independently H, methyl, ethyl, n-propyl or isopropyl.
  • X is independently selected from NH—CO, CH 2 and NH.
  • X is independently selected from NH—CO and CH 2 .
  • X is CH2 .
  • J 2 is H or methyl. In some embodiments, J is H.
  • R is selected from H and methyl.
  • R2 is selected from H, methyl, and CH2OH .
  • R1 and R2 are directly linked to form a 5-6 membered ring. In some embodiments, R and R are directly connected to form a 3-6 membered cycloalkyl. In some embodiments, R 1 and R 2 are directly connected to form cyclopentyl or cyclohexyl.
  • the chemical modification represented by the formula (I) is selected from any of the following structures:
  • B is selected from purine base, pyrimidine base, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification represented by the formula (I) is selected from any of the following structures:
  • B is selected from purine base, pyrimidine base, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification represented by the formula (I) is selected from any of the following structures:
  • B is selected from purine base, pyrimidine base, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from the group consisting of adenine, guanine, isoguanine, hypoxanthine, xanthine, C2-modified purine, N8-modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, heterocytosine Pyrimidine, pseudocytosine, uracil, pseudouracil, 2-thiouridine, 4-thiouridine, C5-modified pyrimidines, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification represented by the formula (I) is selected from any of the following structures:
  • B is selected from purine base, pyrimidine base, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • nucleotide comprising the chemical modification represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof is selected from nucleotides comprising the chemical modification represented by formula (I'), its tautomer or its pharmaceutically acceptable salt,
  • Y is selected from O, NH and S;
  • Each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • J 2 is H or C 1 -C 6 alkyl
  • Q 1' is Q 2' is R 2 ; or Q 1' is R 2 and Q 2' is
  • J 1 is H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a ring
  • B is a base
  • M is O or S
  • R when X is NH-CO, R is not H.
  • the chemical modification represented by formula (I'), its tautomer, or a pharmaceutically acceptable salt thereof is replaced with a 2'-methoxy modification.
  • the chemical modification shown in the formula (I') is selected from the chemical modification shown in the formula (I'-1):
  • Y is selected from O, NH and S;
  • Each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • Each J 1 and J 2 are independently H or C 1 -C 6 alkyl
  • M is O or S
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification shown in formula (I') is selected from the chemical modification shown in formula (I'-2):
  • Y is selected from O, NH and S;
  • Each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • Each J 1 and J 2 are independently H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a ring
  • M is O or S
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are each independently H or C 1 -C 3 alkyl;
  • Each J 1 and J 2 are independently H or C 1 -C 3 alkyl
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • each X is independently selected from CR 4 (R 4 '), S, NR 5 and NH-CO, wherein R 4 , R 4 ', R 5 are each independently H, methyl, ethyl, n-propyl or isopropyl;
  • Each J 1 and J 2 are independently H or methyl
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2-thiouridine, 4-thiouridine, C5-modified pyrimidines, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Each J 1 and J 2 are independently H;
  • R 1 is selected from H, methyl and CH 2 OH;
  • R 2 is selected from H, methyl and CH 2 OH;
  • R 3 is selected from H, OH, NH 2 , methyl and CH 2 OH;
  • R 1 and R 2 are directly connected to form a ring
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Y is O or NH
  • Each X is independently selected from CR 4 (R 4 '), NR 5 and NH-CO, R 4 , R 4 ', R 5 are independently H or C 1 -C 6 alkyl;
  • J 2 is H or C 1 -C 6 alkyl
  • R 3 is selected from H, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy and (CH 2 ) p R 6 ;
  • Q 1' for Q 2' is R 2 ; or Q 1' is R 2 and Q 2' is
  • R 1 is selected from H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and (CH 2 ) q R 7 ;
  • J 1 is H or C 1 -C 6 alkyl
  • R 2 is selected from H, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and (CH 2 ) r R 8 ;
  • R 1 and R 2 are directly connected to form a 3-6 membered ring;
  • M is O or S
  • B is a base
  • X is independently selected from CR 4 (R 4 ′) and NH—CO.
  • X is independently selected from CR 4 (R 4 ′).
  • R 3 is selected from H, C 1 -C 6 alkyl, and (CH 2 ) p R 6 .
  • R 3 is selected from H and C 1 -C 6 alkyl.
  • R 1 is selected from H, C 1 -C 6 alkyl, and (CH 2 ) q R 7 .
  • R 1 is selected from H and C 1 -C 6 alkyl.
  • R 2 is selected from H, OH, C 1 -C 6 alkyl, and (CH 2 ) r R 8 .
  • R 2 is selected from H, C 1 -C 6 alkyl, and (CH 2 ) r R 8 .
  • Y is O
  • Each X is independently selected from CR 4 (R 4 ') and NH-CO, R 4 and R 4 ' are independently H or C 1 -C 6 alkyl;
  • J 2 is H or C 1 -C 6 alkyl
  • R 3 is selected from H, C 1 -C 6 alkyl and (CH 2 ) p R 6 ;
  • Q 1' for Q 2' is R 2 ; or Q 1' is R 2 and Q 2' is
  • R 1 is selected from H, C 1 -C 6 alkyl and (CH 2 ) q R 7 ;
  • J 1 is H or C 1 -C 6 alkyl
  • R 2 is selected from H, OH, C 1 -C 6 alkyl and (CH 2 ) r R 8 ;
  • R 1 and R 2 are directly connected to form a 5-6 membered ring;
  • M is O or S
  • B is a base
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Y is O
  • Each X is independently selected from CR 4 (R 4 '), R 4 and R 4 ' are independently H or C 1 -C 6 alkyl;
  • R 3 is selected from H and C 1 -C 6 alkyl
  • Q 1' for Q 2' is R 2 ; or Q 1' is R 2 and Q 2' is
  • R 1 is selected from H and C 1 -C 6 alkyl
  • J 1 is H or C 1 -C 6 alkyl
  • R 1 and R 2 are directly connected to form a 5-6 membered ring;
  • M is O or S
  • B is a base
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylamino Purine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • Y is O.
  • X is independently selected from CR 4 (R 4 ′), NR 5 and NH-CO, and R 4 , R 4 ′, and R 5 are each independently H, methyl, ethyl, n-propyl or isopropyl.
  • X is independently selected from NH—CO, CH 2 and NH.
  • X is independently selected from NH—CO and CH 2 .
  • X is CH2 .
  • J 2 is H or methyl. In some embodiments, J is H.
  • R is selected from H and methyl.
  • R2 is selected from H, methyl, and CH2OH .
  • R1 and R2 are directly linked to form a 5-6 membered ring. In some embodiments, R and R are directly connected to form a 3-6 membered cycloalkyl. In some embodiments, R 1 and R 2 are directly connected to form cyclopentyl or cyclohexyl.
  • the chemical modification represented by the formula (I') is selected from any of the following structures:
  • M is O or S
  • B is selected from purine bases, pyrimidine bases, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification represented by the formula (I') is selected from any of the following structures:
  • M is O or S
  • B is selected from purine bases, pyrimidine bases, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification represented by the formula (I') is selected from any of the following structures:
  • M is O or S
  • B is selected from purine bases, pyrimidine bases, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same base as if the nucleotide at that position on the antisense strand was unmodified.
  • the chemical modification represented by the formula (I') is selected from any of the following structures: and those in which the adenine in their structure is replaced by guanine, cytosine, uracil, or thymine.
  • B is selected from the group consisting of purine bases, pyrimidine bases, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, isoguanine, hypoxanthine, xanthine, C2 modified purine, N8 modified purine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, N6-alkyladenine, O6-alkylguanine, 7-deazapurine, cytosine, 5-methylcytosine, isocytosine, pseudocytosine, uracil, pseudouracil, 2- Thiouridine, 4-thiouridine, C5-modified pyrimidine, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole, and 3-nitropyrrole.
  • B is the same as the base of the antisense strand when the nucleotide at this position is unmodified.
  • the present disclosure provides a dsRNA comprising a sense strand and an antisense strand:
  • the antisense strand is at least partially reverse complementary to the target sequence; in some embodiments, there are no more than 5, no more than 4, no more than 3, no more than 2, and no more than 1 mismatches between the antisense strand and the target sequence; in some embodiments, the antisense strand is fully reverse complementary to the target sequence.
  • the sense strand and the antisense strand are at least partially reverse complementary to form a double-stranded region; in some embodiments, there are no more than 5, no more than 4, no more than 3, no more than 2, and no more than 1 mismatches between the sense strand and the antisense strand; in some embodiments, the sense strand and the antisense strand are fully reverse complementary.
  • the sense and antisense strands each independently have 16 to 35, 16 to 34, 17 to 34, 17 to 33, 18 to 33, 18 to 32, 18 to 31, 18 to 30, 18 to 29, 18 to 28, 18 to 27, 18 to 26, 18 to 25, 18 to 24, 18 to 23, 19 to 25, 19 to 24, or 19 to 23 nucleotides (eg, 19, 20, 21, 22, 23 nucleotides).
  • the sense strand and the antisense strand are the same or different in length, the sense strand is 19-23 nucleotides in length, and the antisense strand is 19-26 nucleotides in length.
  • the length ratio of the sense strand and the antisense strand may be 19/19, 19/20, 19/21, 19/22, 19/23, 19/24, 19/25, 19/26, 20/19, 20/20, 20/21, 20/22, 20/23, 20/24, 20/25, 20/26, 21/20, 2 1/21, 21/22, 21/23, 21/24, 21/25, 21/26, 22/20, 22/21, 22/22, 22/23, 22/24, 22/25, 22/26, 23/20, 23/21, 23/22, 23/23, 23/24, 23/25, or 23/26.
  • the sense and antisense strands have a length ratio of 19/21, 21/23, or 23/25.
  • the dsRNA comprises one or two blunt ends.
  • the dsRNA comprises an overhang with 1 to 4 unpaired nucleotides, eg, 1, 2, 3, 4.
  • the dsRNA comprises an overhang located 3' to the antisense strand.
  • the nucleotide comprising the chemical modification represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof is located at position 5, position 6 or position 7 of the 5' region of the antisense strand.
  • the nucleotide comprising the chemical modification represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof is located at position 7 of the 5' region of the antisense strand.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole and 3-nitropyrrole.
  • B is selected from adenine, guanine, 2,6-diaminopurine, 6-dimethylaminopurine, 2-aminopurine, cytosine, uracil, thymine, indole, 5-nitroindole and 3-nitropyrrole.
  • B is the same as the base of the antisense strand when the 5th nucleotide in its 5' region is not modified.
  • B is the same as the base when the 6th nucleotide of the 5' region of the antisense strand is not modified.
  • B is the same as the base of the antisense strand when the 7th nucleotide in the 5' region thereof is unmodified.
  • the nucleotide at position 5 of the sense strand is a 2'-methoxy modified nucleotide.
  • the 7th nucleotide of the antisense strand is a 2'-methoxy modified nucleotide.
  • the sense strand and the antisense strand comprise or are nucleotide sequences represented by the following formula:
  • Antisense strand 5'-N a 'N b 'N a 'X'N a 'X'W'X'X'X'N a 'X'N a 'N b 'N a 'X'N a 'X'N a 'N a '-3';
  • each X is independently Na or Nb
  • each X' is independently Na ' or Nb '
  • Na and Na ' are 2'-methoxy-modified nucleotides
  • Nb and Nb ' are 2'-fluoro-modified nucleotides
  • W' represents a 2'-methoxy-modified nucleotide or a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof.
  • W' represents a 2'-methoxy modified nucleotide.
  • W' represents a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof, and in some embodiments, W' has the following structure:
  • the sense strand and the antisense strand comprise or are nucleotide sequences represented by the following formula:
  • Antisense strand 5'-N a 'N b 'N a 'X'N a 'X'W'X'X'X'N a 'X'N a 'N b 'N a 'X'N a 'X'N a 'N a '-3';
  • each X' is independently N a ' or N b '; N a and N a ' are 2'-methoxy-modified nucleotides, N b and N b ' are 2'-fluoro-modified nucleotides;
  • W' represents a 2'-methoxy-modified nucleotide or a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof.
  • W' represents a 2'-methoxy modified nucleotide.
  • W' represents a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof, and in some embodiments W' has the following structure:
  • the sense strand comprises or is a nucleotide sequence as shown in the following formula:
  • X is Na or N b ;
  • Na is a 2'-methoxy modified nucleotide, and
  • N b is a 2'-fluoro modified nucleotide.
  • the sense strand comprises or is a nucleotide sequence represented by the following formula:
  • N a is a 2'-methoxy-modified nucleotide
  • N b is a 2'-fluoro-modified nucleotide
  • the antisense strand comprises or is a nucleotide sequence represented by the following formula:
  • each X' is independently N a ' or N b ';
  • N a ' is a 2'-methoxy-modified nucleotide, and
  • N b ' is a 2'-fluoro-modified nucleotide;
  • W' represents a 2'-methoxy-modified nucleotide or a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof.
  • W' represents a 2'-methoxy modified nucleotide.
  • W' represents a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof, and in some embodiments W' has the following structure:
  • the chemical modification represented by formula (I) is selected from:
  • B is selected from guanine, adenine, cytosine and uracil; in some specific embodiments, B is the same as the base when the 7th nucleotide in the 5' region of the antisense strand is not modified.
  • the chemical modification represented by formula (I) is selected from:
  • M is O or S;
  • B is selected from guanine, adenine, cytosine or uracil; In some specific embodiments, B is the same as the base when the 7th nucleotide in the 5' region of the antisense strand is not modified.
  • M is S. In some specific embodiments, M is O.
  • the antisense strand comprises or is a nucleotide sequence represented by the following formula:
  • N a ' is a 2'-methoxy-modified nucleotide
  • N b ' is a 2'-fluoro-modified nucleotide
  • W' represents a 2'-methoxy-modified nucleotide or a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof.
  • W' represents a 2'-methoxy modified nucleotide.
  • W' represents a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof, and in some embodiments W' has the following structure:
  • the chemical modification represented by formula (I) is selected from:
  • B is selected from guanine, adenine, cytosine and uracil; in some specific embodiments, B is the same as the base when the 7th nucleotide in the 5' region of the antisense strand is not modified.
  • the chemical modification represented by formula (I) is selected from:
  • M is O or S;
  • B is selected from guanine, adenine, cytosine or uracil; In some specific embodiments, B is the same as the base when the 7th nucleotide in the 5' region of the antisense strand is not modified.
  • M is S. In some specific embodiments, M is O.
  • At least one phosphate group in the sense strand and/or antisense strand is a phosphate group with a modification group, which makes the dsRNA have increased stability in a biological sample or environment; in some embodiments, the phosphate group with a modification group is a phosphorothioate group. In some embodiments, the phosphate group with a modifying group is a phosphorothioate group.
  • the phosphorothioate group is present in at least one of the following positions:
  • the sense strand and/or antisense strand include multiple phosphorothioate groups present in:
  • the sense strand comprises a nucleotide sequence represented by the following formula:
  • Nm represents any nucleotide modified by 2'-methoxy, such as C, G, U, A modified by 2'-methoxy
  • Nf represents any nucleotide modified by 2'-fluoro, such as C, G, U, A modified by 2'-fluoro
  • the lowercase letter s When the lowercase letter s is in the middle, it means that there is a phosphorothioate group connection between the two nucleotides adjacent to the left and right of the letter s; when the lowercase letter s is the first at the 3' end, it means that the end of a nucleotide adjacent to the left side of the letter s is a phosphorothioate group.
  • the sense strand comprises a nucleotide sequence represented by the following formula:
  • Nm represents any nucleotide modified by 2'-methoxy, such as C, G, U, A modified by 2'-methoxy
  • Nf represents any nucleotide modified by 2'-fluoro, such as C, G, U, A modified by 2'-fluoro
  • the lowercase letter s When the lowercase letter s is in the middle, it means that there is a phosphorothioate group connection between the two nucleotides adjacent to the left and right of the letter s; when the lowercase letter s is the first at the 3' end, it means that the end of a nucleotide adjacent to the left side of the letter s is a phosphorothioate group.
  • the antisense strand comprises or is a nucleotide sequence represented by the following formula:
  • Nm' represents any nucleotide modified by 2'-methoxy, such as C, G, U, A modified by 2'-methoxy
  • Nf' represents any nucleotide modified by 2'-fluoro, such as C, G, U, A modified by 2'-fluoro
  • the lowercase letter s When the lowercase letter s is in the middle, it means that there is a phosphorothioate group connection between the two nucleotides adjacent to the left and right of the letter s, and when the lowercase letter s is the first at the 3' end, it means that the end of a nucleotide adjacent to the left side of the letter s is a phosphorothioate group;
  • W' represents a 2'-methoxy modified nucleotide or a modified nucleotide comprising a chemical modification represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof.
  • W' represents a 2'-methoxy modified nucleotide.
  • W' represents a nucleotide comprising a chemical modification represented by formula (I), a tautomer or a pharmaceutically acceptable salt thereof.
  • the chemical modification represented by formula (I) is selected from:
  • B is selected from guanine, adenine, cytosine and uracil; in some embodiments, B is the same as the base when the 7th nucleotide in the 5' region of the antisense strand is not modified.
  • the chemical modification shown in formula (I) is selected from:
  • M is O or S;
  • B is selected from guanine, adenine, cytosine or uracil; In some specific embodiments, B is the same as the base when the 7th nucleotide in the 5' region of the antisense strand is not modified.
  • M is S. In some specific embodiments, M is O.
  • the dsRNA inhibits the expression of angiotensinogen (AGT).
  • AGT angiotensinogen
  • the sense strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO:1 by no more than 3 nucleotides, and/or,
  • the antisense strand comprises at least 19 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO:2 by no more than 3 nucleotides.
  • the sense strand comprises or is selected from the nucleotide sequence of SEQ ID NO:1, and/or, the antisense strand comprises or is selected from the nucleotide sequence of SEQ ID NO:2.
  • the sense strand of the dsRNA comprises or consists of SEQ ID NO:3, and the antisense strand comprises or consists of any nucleotide sequence in SEQ ID NO:5 to SEQ ID NO:15;
  • the dsRNA is any of the following:
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:5;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:6;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:7 sequence;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:8;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:9;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:10;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:11;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:12;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:13;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:14; or
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:3, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:15.
  • the dsRNA is any of the following:
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:5;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:6;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:7;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:8;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:9;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:10;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:11;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:12;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:13;
  • nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:14;
  • the nucleotide sequence of the sense strand consists of SEQ ID NO:3, and the nucleotide sequence of the antisense strand consists of SEQ ID NO:15.
  • the dsRNA is any of the following:
  • the dsRNA is any of the following:
  • SEQ ID NO:10 is N-(SEQ ID NO:10).
  • SEQ ID NO: 11 is N-(SEQ ID NO: 11
  • SEQ ID NO: 12 is
  • SEQ ID NO: 13 is
  • SEQ ID NO: 14 is
  • SEQ ID NO:15 is N-(SEQ ID NO:15).
  • NAG0052' means (-)hmpNA(C) means
  • the dsRNA further comprises a conjugated ligand selected from liver-targeting targeting ligands; in some embodiments, the ligand binds asialoglycoprotein receptor (ASGPR); in some embodiments, the ligand comprises a galactose cluster or a galactose derivative cluster selected from N-acetyl-galactosamine, N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, or N-isobutyrylgalactosamine, or a combination thereof.
  • ASGPR asialoglycoprotein receptor
  • the dsRNA further includes a ligand conjugated thereto, and the ligand is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • R 13 is a single or double bond, and when When it is a single bond, R 13 is independently CR 17 R 18 , NR 16 , O or S, when When it is a double bond, R 13 is independently CR 19 or N;
  • R 14 is independently CR 19 or N;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, present or absent, and when Ring A exists, R 15 is independently CR 19 or N, and when Ring A does not exist, R 15 is independently CR 17 R 18 , NR 16 or O;
  • R' and R" are independently hydrogen, deuterium, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl optionally substituted by one or more substituents selected from halogen, hydroxy, oxo, nitro and cyano;
  • n1, p1 and q1 are independently 0, 1, 2, 3 or 4;
  • z1, z2, z3, z4, z5, z6, z7, z8 and z9 are independently an integer of 0-10;
  • r1 is an integer of 1-10.
  • R 16 is hydrogen or C 1-6 alkyl
  • R 13 is CR 17 R 18 , NR 16 , O or S;
  • R 14 is CR 19 ;
  • R 15 is independently CR 17 R 18 , NR 16 or O;
  • R 17 to R 19 are independently hydrogen, deuterium or alkyl
  • m1, p1 and q1 are independently 0, 1, 2, 3 or 4;
  • z5, z6, z7, z8 and z9 are independently an integer of 0-10;
  • r1 is an integer of 1-10.
  • R 16 is hydrogen or C 1-6 alkyl
  • R 13 is CR 17 R 18 or O
  • R 14 is CR 19 ;
  • R 15 is independently CR 17 R 18 or O;
  • R 17 to R 19 are independently hydrogen or alkyl
  • n 1;
  • z8 and z9 are independently an integer of 0-10;
  • L 2 is -(CH 2 ) j15 -(OCH 2 CH 2 ) 1-4 -(CH 2 ) j16 - or
  • j15 and j16 are independently an integer of 0-4;
  • r1 is 3, 4, 5 or 6.
  • j11, j12, j13, and j14 are independently integers from 0-2 or 4-10. In some embodiments, j11, j12, j13, and j14 are independently 0, 1, 2, 6, 7, 8, 9, or 10.
  • L can be The definition of j12 is the same as that described in the previous scheme, wherein the terminal a1 is connected to B1 , and the terminal b1 is connected to R11 .
  • L can be Wherein, terminal a1 is connected to B1 , and terminal b1 is connected to R11 .
  • R 11 can be a chemical bond and R 12 can be NR 16 , and the definition of R 16 is the same as described in any of the previous schemes.
  • R 16 can be hydrogen or C 1-6 alkyl.
  • R 16 can be hydrogen, methyl, ethyl, propyl, or isopropyl.
  • R 16 can be hydrogen
  • R 17 and R 18 can be hydrogen.
  • R 19 can be hydrogen
  • ring A when present, can be a C 6-12 aryl.
  • ring A can be phenyl
  • m1 can be 0 or 1.
  • m1 can be 3.
  • n1 can be 0 or 1.
  • p1 and q1 are independently 0 or 1.
  • z1, z2, z3, z4, z5, z6, z7, z8, and z9 can independently be an integer from 0-4. In some embodiments, z1, z2, z3, z4, z5, z6, z7, z8, and z9 can be 0, 1, or 2 independently.
  • B 1 can be any organic compound
  • B 1 can be any organic compound
  • B 1 can be any organic compound
  • L 2 can be -(CH 2 ) j15 -(OCH 2 CH 2 ) 1-4 -(CH 2 ) j16 -, j15 and j16 are as defined in the previous scheme.
  • L2 can be In some embodiments, L2 can be Among them, the left side is connected with O atom, and the right side is connected with B1 .
  • L 2 can be a C 1 -C 12 alkyl chain.
  • L2 can be any organic compound
  • L2 can be In some embodiments, L2 can be In some embodiments, L2 can be In some embodiments, L2 can be In some embodiments, L2 can be Among them, the a3 end is connected to the O atom, and the b3 end is connected to the B1 .
  • L2 can be Among them, the a3 end is connected to the O atom, and the b3 end is connected to the B1 .
  • r1 can be 3, 4, 5 or 6. In some embodiments, r1 can be 3.
  • Q3 can be In some embodiments, Q3 can be Wherein, the definitions of R 13 , R 14 , R 15 and n1 are the same as those described in the previous scheme.
  • R 13 , R 14 , R 15 , p1 and q1 are the same as those described in the previous scheme.
  • R 13 , R 14 , R 15 , p1 and q1 are the same as those described in the previous scheme.
  • R 13 , R 14 , n1 The definitions of p1 and q1 are the same as those described in the previous scheme.
  • R 13 , R 14 , n1, p1 and q1 are the same as those described in the previous scheme.
  • Can be The definitions of n1, p1 and q1 are the same as those described in the previous scheme.
  • the ligand can be any of the following structures or a pharmaceutically acceptable salt thereof,
  • the ligand can be any of the following structures or a pharmaceutically acceptable salt thereof,
  • the ligand can be the following structure or a pharmaceutically acceptable salt thereof,
  • the N-acetyl-galactosamine moiety in the above ligands can be replaced with N-trifluoroacetylgalactosamine, N-propionylgalactosamine, N-n-butyrylgalactosamine, or N-isobutyrylgalactosamine.
  • the chemical modification represented by the formula (I) is B is selected from guanine, adenine, cytosine and uracil;
  • the ligand is any of the following structures or a pharmaceutically acceptable salt thereof,
  • the definitions of the sense strand and the antisense strand are as described in any of the previous schemes.
  • the chemical modification represented by the formula (I) is B is selected from guanine, adenine, cytosine and uracil;
  • the ligand is any of the following structures or a pharmaceutically acceptable salt thereof,
  • the definitions of the sense strand and the antisense strand are as described in any of the previous schemes.
  • the chemical modification represented by the formula (I) is B is selected from guanine, adenine, cytosine and uracil;
  • the ligand is the following structure or a pharmaceutically acceptable salt thereof,
  • the definitions of the sense strand and the antisense strand are as described in any of the previous schemes.
  • the sense strand and/or antisense strand and the ligand are covalently or non-covalently linked.
  • the 3' end and/or the 5' end of the sense strand is conjugated to the ligand.
  • the 3' end of the sense strand is conjugated to the ligand.
  • the ligand is attached to the end of the sense strand and/or the antisense strand via a phosphate group or a phosphorothioate group.
  • the ligand is attached to the end of the sense strand and/or the antisense strand via a phosphodiester group or a phosphorothioate group.
  • the ligand binds to the end of the sense strand and/or the antisense strand through a phosphodiester group. end connection.
  • the ligand is indirectly linked to the end of the sense strand and/or antisense strand via a phosphate group or a phosphorothioate group.
  • the ligand is directly linked to the end of the sense strand and/or antisense strand via a phosphate group or a phosphorothioate group.
  • the ligand is directly attached to the 3' end of the sense strand via a phosphate group or a phosphorothioate group.
  • the phosphate group is a phosphate monoester group or a phosphodiester group. In some embodiments, the phosphate group is a phosphodiester group.
  • the phosphorothioate group is a phosphorothioate monoester group or a phosphorothioate diester group. In some embodiments, the phosphorothioate group is a phosphorothioate diester group.
  • a lipophilic group such as cholesterol can be introduced at the end of the sense strand.
  • the lipophilic group includes binding to small interfering nucleic acid with a covalent bond, such as introducing cholesterol, lipoprotein, vitamin E, etc. at the end, so as to facilitate the interaction with mRNA in the cell through the cell membrane composed of lipid bilayer.
  • dsRNA can also be modified by non-covalent bonds, such as binding phospholipid molecules, polypeptides, and cationic polymers through hydrophobic bonds or ionic bonds to increase stability and biological activity.
  • the number of ligands includes but is not limited to: 1, 2, 3 or 4. In some embodiments, the number of the ligand is 1.
  • the nucleotide sequence of the sense strand of the dsRNA comprises or consists of SEQ ID NO:4, and the nucleotide sequence of the antisense strand comprises or consists of any nucleotide sequence of SEQ ID NO:5 to SEQ ID NO:15;
  • the dsRNA is any of the following:
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:5;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:6;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:7;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:8;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:9;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:10;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:11;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:12;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:13;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:14;
  • the sense strand comprises the nucleotide sequence of SEQ ID NO:4, and the antisense strand comprises the nucleotide sequence of SEQ ID NO:15.
  • the dsRNA is any of the following:
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:5;
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:6;
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:7;
  • the sense strand is composed of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is composed of the nucleotide sequence shown in SEQ ID NO:8;
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:9;
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:10;
  • the sense strand is composed of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is composed of the nucleotide sequence shown in SEQ ID NO:11;
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:12;
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:13;
  • the sense strand consists of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand consists of the nucleotide sequence shown in SEQ ID NO:14; or
  • the sense strand is made up of the nucleotide sequence shown in SEQ ID NO:4, and the antisense strand is made up of the nucleotide sequence shown in SEQ ID NO:15.
  • the dsRNA is any of the following:
  • the dsRNA is any of the following:
  • the sense strand consisting of SEQ ID NO:4 and any one of SEQ ID NO:5 to SEQ ID NO:15 composed antisense strand.
  • SEQ ID NO:10 is N-(SEQ ID NO:10).
  • SEQ ID NO: 11 is N-(SEQ ID NO: 11
  • SEQ ID NO: 12 is
  • SEQ ID NO: 13 is
  • SEQ ID NO: 14 is
  • SEQ ID NO:15 is N-(SEQ ID NO:15).
  • NAG0052' means (-)hmpNA(C) means
  • the dsRNA is selected from the following structures or pharmaceutically acceptable salts thereof:
  • the pharmaceutically acceptable salts can be conventional salts in the art, including but not limited to: sodium salts, potassium salts, ammonium salts, amine salts and the like.
  • the dsRNA is selected from any one of TRD008110, TRD008112, TRD008103, TRD008104, TRD008105, TRD008106, TRD008107, TRD008108, TRD008109, TRD008111, TRD008113.
  • the dsRNA is TRD008110, which has the following structure:
  • the dsRNA is TRD008112, which has the following structure:
  • the present disclosure provides a pharmaceutical composition comprising the dsRNA described in the present disclosure.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  • Various delivery systems are known and can be used with the dsRNA or pharmaceutical compositions of the present disclosure, such as encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis, constructed nucleic acid as part of a retrovirus or other vector.
  • the administration of the dsRNA or the pharmaceutical composition of the present disclosure is conventional, and can be administered locally (for example, direct injection or implantation) or systemically, and can also be administered orally, rectally or parenterally.
  • a dsRNA or pharmaceutical composition provided herein can be administered by injection, eg, intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal injection.
  • the dsRNA or pharmaceutical compositions provided by the present disclosure can be packaged in kits.
  • the effective amount or effective dose of the dsRNA or the pharmaceutical composition is about 0.001 mg/kg body weight to about 200 mg/kg body weight, about 0.01 mg/kg body weight to about 100 mg/kg body weight, or about 0.5 mg/kg body weight to about 50 mg/kg body weight.
  • the present disclosure provides an application of the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure in the preparation of medicine.
  • the medicament can be used to prevent and/or treat hypertension, cardiovascular disease or hepatic disease.
  • the drug can be used to prevent and/or treat borderline hypertension, Essential hypertension, secondary hypertension, isolated systolic or diastolic hypertension, pregnancy-related hypertension, diabetic hypertension, resistant hypertension, resistant hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, unstable hypertension, hypertensive heart disease, hypertensive nephropathy, atherosclerosis, arteriosclerosis, vascular disease, diabetic nephropathy, Diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiomyopathy, glomerulosclerosis, coarctation of the aorta, aortic
  • the medicament can be used to prevent and/or treat diseases related to AGT gene expression.
  • the disease associated with AGT gene expression may be hypertension, cardiovascular disease or hepatic disease.
  • the disease may be borderline hypertension, essential hypertension, secondary hypertension, isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, unstable hypertension, hypertensive heart disease, hypertensive nephropathy, atherosclerosis arteriosclerosis, vascular disease, diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiomyopathy, glomerulos
  • the effective amount or effective dose of the dsRNA or the pharmaceutical composition is about 0.001 mg/kg body weight to about 200 mg/kg body weight, about 0.01 mg/kg body weight to about 100 mg/kg body weight, or about 0.5 mg/kg body weight to about 50 mg/kg body weight.
  • the present disclosure provides a method for preventing and/or treating a disease, which comprises administering to a subject an effective amount or dose of the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure.
  • the disease may be hypertension, cardiovascular disease, or hepatic disease.
  • the disease may be hypertension, essential hypertension, secondary hypertension, isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, resistant hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, unstable hypertension, hypertensive heart disease Heart disease, hypertensive nephropathy, atherosclerosis, arteriosclerosis, vascular disease, diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiomyopathy, glomerulosclerosis, coarctation of the aorta, aortic aneurysm, ventricular fibrosis, heart
  • the disease may be a disease associated with AGT gene expression.
  • the disease associated with AGT gene expression may be hypertension, cardiovascular disease or hepatic disease.
  • the disease may be borderline hypertension, essential hypertension, secondary hypertension, isolated systolic or diastolic hypertension, pregnancy-associated hypertension, diabetic hypertension, resistant hypertension, refractory hypertension, paroxysmal hypertension, renovascular hypertension, Goldblatt's hypertension, hypertension associated with low plasma renin activity or plasma renin concentration, ocular hypertension, glaucoma, pulmonary hypertension, portal hypertension, systemic venous hypertension, systolic hypertension, unstable hypertension, hypertensive heart disease, hypertensive nephropathy, atherosclerosis arteriosclerosis, vascular disease, diabetic nephropathy, diabetic retinopathy, chronic heart failure, cardiomyopathy, diabetic cardiomyopathy, glomerulosclerosis, coarctation
  • the present disclosure provides a method for silencing a target gene or its mRNA in a cell in vivo or in vitro, comprising the step of introducing the dsRNA of the present disclosure or the pharmaceutical composition of the present disclosure into the cell.
  • the target gene is AGT.
  • the present disclosure provides a method for inhibiting the expression of a target gene or its mRNA, which comprises administering an effective amount or dose of the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure to a subject.
  • the target gene is AGT.
  • the dsRNA or pharmaceutical composition of the present disclosure can reduce the expression level of a target gene or its mRNA in a cell, cell group, tissue or subject, including: administering a therapeutically effective amount of the dsRNA or the pharmaceutical composition described herein to the subject, thereby inhibiting the expression of the target gene or its mRNA in the subject.
  • the subject has been previously identified as having pathological upregulation of the target gene or its mRNA in the targeted cell, cell population, tissue or subject.
  • the present disclosure provides a method of delivering an oligonucleotide to the liver, which comprises administering to a subject an effective amount or dose of the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure.
  • the present disclosure provides an RNA interference (RNAi) agent comprising the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure.
  • RNAi RNA interference
  • the present disclosure also provides a cell comprising the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure.
  • the present disclosure also provides a kit comprising the dsRNA described in the present disclosure or the pharmaceutical composition described in the present disclosure.
  • the dsRNAs of the present disclosure are selected from siRNAs.
  • the dsRNA or the pharmaceutical composition of the present disclosure when the dsRNA or the pharmaceutical composition of the present disclosure contacts cells expressing the target gene, the dsRNA or the pharmaceutical composition of the present disclosure can inhibit the expression of the target gene by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 20%, at least 25%, or at least as determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA)-based methods, or protein-based methods, such as immunofluorescence analysis, such as Western Blot or flow cytometry.
  • bDNA branched DNA
  • protein-based methods such as immunofluorescence analysis, such as Western Blot or flow cytometry.
  • At least 35% at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.
  • the remaining expression percentage of the target gene mRNA caused by the dsRNA or the pharmaceutical composition of the present disclosure is not higher than 99%, not higher than 95%, not higher than 90%, and not higher than 8, as determined by, for example: psiCHECK activity screening and luciferase reporter gene detection method, other methods such as PCR or based on branched DNA (bDNA), or protein-based methods, such as immunofluorescence analysis, such as Western Blot or flow cytometry.
  • the dsRNA when the dsRNA or the pharmaceutical composition of the present disclosure contacts cells expressing the target gene, the dsRNA reduces the off-target activity by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, while maintaining the target activity, as determined by, for example, psiCHECK activity screening and luciferase reporter gene assay, other methods such as PCR or branched DNA (bDNA)-based methods, or protein-based methods, such as immunofluorescence analysis, such as Western Blot, or flow cytometry. %, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.
  • the dsRNA or the pharmaceutical composition of the present disclosure when exposed to cells expressing the target gene, the dsRNA reduces the activity on the target by at most 20%, at most 19%, at most 15%, at most 10%, at most 5%, or more than 1%, as determined by, for example, psiCHECK activity screening and luciferase reporter gene assays, other methods such as PCR or branched DNA (bDNA)-based methods, or protein-based methods, such as immunofluorescence assays, such as Western Blot, or flow cytometry.
  • psiCHECK activity screening and luciferase reporter gene assays other methods such as PCR or branched DNA (bDNA)-based methods, or protein-based methods, such as immunofluorescence assays, such as Western Blot, or flow cytometry.
  • off-target activity is reduced by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.
  • dsRNA or the pharmaceutical composition of the present disclosure contacts the cells expressing the target gene
  • the target gene for example: psiCHECK activity screening and luciferase reporter gene detection method
  • other methods such as PCR or analysis-based dsRNA increases on-target activity by at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% while reducing off-target activity by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75%.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomers are recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization (eg, carbamates from amines).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • the bond configuration is not specified, i.e. the key The configuration of can be E type or Z type, or contain both E and Z configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • interconversions via migration of a proton such as keto-enol and imine-enamine, lactam-lactam isomerizations.
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N, 15O , 17O , 18O, 31P , 32P , 35S , 18F , 123I , 125I , and 36Cl , respectively . wait.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes compounds of Formula (I), Formula (I'), Formula (II) in various deuterated forms.
  • deuterated forms of formula (I), formula (I '), formula (II) compounds can be synthesized using conventional techniques using deuterated reagents, deuterated reagents include but not limited to deuterated borane, trideuterioborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • the present disclosure also provides a method for preparing dsRNA or a pharmaceutical composition, which includes: synthesizing the dsRNA or the pharmaceutical composition described in the present disclosure.
  • the term “comprising” or “comprising” means including stated elements, integers or steps, but not excluding any other elements, integers or steps.
  • the term “comprising” or “comprises” is used, unless otherwise specified, it also covers the situation consisting of the mentioned elements, integers or steps.
  • a reference is made to “comprising” a specific sequence it is also intended to cover the situation consisting of that specific sequence.
  • the "compound”, “chemical modification”, “ligand”, “dsRNA”, “nucleic acid” and “RNAi” of the present disclosure can independently exist in the form of salt, mixed salt or non-salt (such as free acid or free base).
  • a salt or mixed salt it may be a pharmaceutically acceptable salt.
  • “Pharmaceutically acceptable salt” may be selected from inorganic salts or organic salts, and may also include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, Oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-to
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • the inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts, and in some embodiments are sodium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, Lucaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc.
  • Organic bases in some embodiments include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl
  • Alkyl refers to a saturated aliphatic hydrocarbon group, such as a straight chain and branched chain group (C 1 -C 30 alkyl) including 1 to 30 carbon atoms, another example is an alkyl group containing 1 to 6 carbon atoms (C 1 -C 6 alkyl), and another example is an alkyl group with 1 to 3 carbon atoms (C 1 -C 3 alkyl).
  • Non-limiting examples include methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched chain isomers, etc.
  • alkenyl refers to a hydrocarbon group containing at least one double bond.
  • alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, or 2-butenyl, and various branched isomers thereof.
  • alkynyl refers to a hydrocarbon group containing at least one triple bond.
  • alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, or 2-butynyl, and various branched isomers thereof.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring contains 3 to 20 carbon atoms, preferably contains 3 to 6 carbon atoms, more preferably contains 5-6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; multicyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • Heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or multicyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms.
  • Non-limiting examples of "heterocycloalkyl” include: etc.
  • heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Aryl means a 6- to 14-membered all-carbon monocyclic or fused polycyclic ring with a conjugated ⁇ -electron system (that is, a shared (ring) groups adjacent to pairs of carbon atoms, preferably 6 to 12 membered, eg phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.
  • the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • the "phosphate group” can be a phosphoric monoester group, a phosphoric diester group or a phosphoric acid triester group, preferably a phosphoric diester group; the "phosphate group” in the “thiophosphoric ester group” also has the same meaning.
  • phosphorothioate group refers to a phosphodiester group modified by replacing a non-bridging oxygen atom with a sulfur atom, which can be used (M is an S atom) are used interchangeably.
  • substitution means that one or more hydrogen atoms in a group, preferably at most 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents.
  • two (2) hydrogens on the atom are replaced.
  • group middle A moiety can be replaced by any group that enables linkage to adjacent nucleotides.
  • connection when referring to a link between two molecules, means that two molecules are connected by a covalent bond or two molecules are associated by a non-covalent bond (eg, a hydrogen bond or an ionic bond), including direct connection, indirect connection.
  • a non-covalent bond eg, a hydrogen bond or an ionic bond
  • directly linked means that a first compound or group is linked to a second compound or group without any intervening atoms or groups of atoms.
  • directly linked means that a first compound or group is linked to a second compound or group through an intervening group, compound or molecule (eg, a linking group).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiologically acceptable salt or prodrug thereof and other chemical components, as well as other components such as physiologically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration (FDA) to be acceptable for use in humans or livestock animals.
  • FDA U.S. Food and Drug Administration
  • the term “inhibit”, is used interchangeably with “reduce”, “silence”, “downregulate”, “suppress” and other similar terms, and includes any level of inhibition. Inhibition can be assessed by a reduction in the absolute or relative level of one or more of these variables compared to control levels.
  • the control level can be any type of control level used in the art, such as a pre-dose baseline level or a level determined from a similar untreated or control-treated subject, cell, or sample, such as a buffer-only control or an inert control.
  • the remaining expression of mRNA can be used to characterize the degree of inhibition of dsRNA on target gene expression, such as the remaining expression of mRNA is not higher than 99%, not higher than 95%, not higher than 90%, not higher than 85%, not higher than 80%, not higher than 75%, not higher than 70%, not higher than 65%, not higher than 60%, not higher than 55%, not higher than 50%, not higher than 45%, not higher than 40%, not higher than 35%, not higher than 30%, not higher than 25% %, not higher than 20%, not higher than 15%, or not higher than 10%.
  • an “effective amount” or “effective dose” includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to permit or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • subject As used herein, “subject”, “patient”, “subject” or “individual” are used interchangeably and include humans or non-human animals such as mammals such as humans or monkeys.
  • AGT angiotensinogen
  • AGT is also known as SERPINA8 and ANHU.
  • AGT includes but is not limited to human AGT, cynomolgus AGT, mouse AGT, rat AGT, and its amino acid and complete coding sequence, mRNA sequence is easy to use the published database to obtain, for example, GenBank, UniProt, OMIM and macaque (Macaca) genome project website.
  • AGT also refers to naturally occurring DNA sequence variations of the AGT gene, such as single nucleotide polymorphisms (SNPs) in the AGT gene.
  • SNPs single nucleotide polymorphisms
  • Exemplary SNPs can be found in the dbSNP database.
  • target sequence refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during transcription of an AGT gene, including mRNA that is a product of RNA processing that is the primary transcription product.
  • the targeted portion of the target sequence should be long enough to serve as a substrate for iRNA-directed cleavage.
  • the target sequence is within the protein coding region of AGT.
  • dsRNA refers to a double-stranded RNA molecule capable of RNA interference, comprising a sense strand and an antisense strand.
  • the sense strand also known as SS, SS strand or sense strand
  • the antisense strand also known as AS or AS strand
  • the term "the nucleotide sequence of SEQ ID NO: 1 differs by at least 15 contiguous nucleotides of no more than 3 nucleotide sequences" is intended to mean that the sense strand of dsRNA as described herein comprises at least 15 contiguous nucleotides of SEQ ID NO: 1, or differs from at least 15 contiguous nucleotides of SEQ ID NO: 1 by no more than 3 nucleotides, optionally by no more than 2 nucleotides, optionally by 1 nucleotide.
  • the dsRNA sense strand described herein comprises at least 16 consecutive nucleotides of SEQ ID NO: 1, or differs from at least 16 consecutive nucleotides of SEQ ID NO: 1 by no more than 3 nucleotide sequences, optionally, differs by no more than 2 nucleotide sequences, optionally, differs by 1 nucleotide sequence;
  • the term "differing from SEQ ID NO:2 by at least 15 consecutive nucleotides of a sequence of nucleotides” is intended to mean at least 15 consecutive nucleotides of SEQ ID NO:2 described herein, or differing from at least 15 consecutive nucleotides of SEQ ID NO:2 by no more than 3 nucleotide sequences, optionally differing by no more than 2 nucleotide sequences, optionally differing by 1 nucleotide sequence.
  • G", “C”, “A”, “T” and “U” respectively represent nucleotides, which respectively contain bases of guanine, cytosine, adenine, thymidine and uracil.
  • the lowercase letter m indicates that the nucleotide adjacent to the left of the letter m is a methoxy-modified nucleotide;
  • the lowercase letter f indicates that the nucleotide adjacent to the left of the letter f is a fluorine-modified nucleotide;
  • the lowercase letter s indicates that the two nucleotides adjacent to the left and right of the letter s are connected by a phosphorothioate group.
  • 2'-fluoro (2'-F) modified nucleotide refers to a nucleotide formed by replacing the hydroxyl group at the 2' position of the ribose group of the nucleotide with fluorine
  • non-fluorinated modified nucleotide refers to a nucleotide or nucleotide analogue formed by replacing the hydroxyl group at the 2' position of the ribosyl group of the nucleotide with a non-fluorine group.
  • 2'-methoxy (2'-OMe) modified nucleotide refers to a nucleotide in which the 2'-hydroxyl group of the ribose group is substituted with a methoxy group.
  • nucleotide difference between a nucleotide sequence and another nucleotide sequence means that the base type of the nucleotide at the same position has changed between the former and the latter. For example, when a nucleotide base in the latter is A, and the corresponding nucleotide base at the same position in the former is U, C, G or T, it is determined that there is a nucleotide difference at this position between the two nucleotide sequences. In some embodiments, a nucleotide difference at a position is also considered to have occurred when an abasic nucleotide or its equivalent is substituted for the nucleotide at that position.
  • the terms "complementary” or “reverse complementary” are used interchangeably and have the meaning known to those skilled in the art, that is, in a double-stranded nucleic acid molecule, bases on one strand pair with bases on the other strand in a complementary manner.
  • the purine base adenine (A) always pairs with the pyrimidine base thymine (or, in RNA, uracil); the purine base guanine always pairs with the pyrimidine base cytosine.
  • Each base pair consists of a purine and a pyrimidine.
  • mismatch in the art means that in a double-stranded nucleic acid, the bases at the corresponding positions are not paired in a complementary form.
  • chemical modification includes all alterations of nucleotides by chemical means, such as the addition or removal of chemical moieties, or the substitution of one chemical moiety for another.
  • base includes any known DNA and RNA base, base analogues such as purine or pyrimidine, which also includes the natural compounds adenine, thymine, guanine, cytosine, uracil, inosine and natural analogues. Base analogs can also be universal bases.
  • blunt end or blunt end are used interchangeably and refer to the absence of unpaired nucleotides or nucleotide analogs at a given end of a dsRNA, ie, no nucleotide overhangs. In most cases, a dsRNA with both blunt-ended ends will be double-stranded throughout its entire length.
  • the dsRNA provided by the present disclosure can be prepared by conventional preparation methods in the art (such as solid phase synthesis and liquid phase synthesis) Synthetic method) obtained. Among them, solid-phase synthesis has commercialized customized services.
  • Modified nucleotide groups can be introduced into the dsRNA described in the present disclosure by using correspondingly modified nucleoside monomers, methods for preparing correspondingly modified nucleoside monomers and methods for introducing modified nucleotide groups into dsRNA are also well known to those skilled in the art.
  • Figure 1 shows the expression levels of TTR mRNA of TRD002218 and TRD007205 on the 7th day after administration.
  • Figure 2 shows the expression levels of TTR mRNA on day 28 after administration of TRD002218 and TRD007205.
  • Embodiment 1 Preparation of chemical modification
  • Racemate compound 6 was passed through a chiral column (Daicel IE 250*4.6mm, 5 ⁇ m, A: n-hexane, B: ethanol) resolved to obtain 410mg 6A(-) and 435mg 6B(+).
  • compound 5 (6.8 g, 18.581 mmol) was dissolved in pyridine (80 mL), and TMSCl (14.250 mL, 111.489 mmol) was slowly added at 0° C., and stirred for 2 h. Then Isobutyryl chloride (2.044 mL, 19.511 mmol) was added at 0°C and stirred at 25°C for 1 h. LCMS showed the reaction was complete.
  • reaction solution was extracted with ethyl acetate (200mL) and water (200mL), the organic phase was dried and spin-dried, and the mixed sample was purified by forward column (PE:EtOAc column, peak at 84%) to obtain yellow oily compound 7 (12g).
  • Embodiment 2 Characterization of different chemical modifications
  • hmpNA from nucleotides synthesized from 2-hydroxymethyl-1,3-propanediol as the starting material
  • (+)hmpNA(A) is obtained by solid-phase synthesis of the nucleoside phosphoramidite monomer 1-1b in Example 1.1, and the absolute configuration is (S)-hmpNA(A);
  • (-)hmpNA(A) is obtained by solid-phase synthesis of nucleoside phosphoramidite monomer 1-1a in Example 1.1, and its absolute configuration is (R)-hmpNA(A);
  • (+)hmpNA(G) the absolute configuration is (S)-hmpNA(G);
  • (+)hmpNA(C) the absolute configuration is (S)-hmpNA(C);
  • (+)hmpNA(U) the absolute configuration is (R)-hmpNA(U);
  • TJ-NA067 The detection crystal is a colorless block (0.30 ⁇ 0.10 ⁇ 0.04mm3), which belongs to the monoclinic crystal system P21 space group.
  • the detection crystal is a colorless block (0.30 ⁇ 0.20 ⁇ 0.10mm3), belonging to the monoclinic crystal system P21 space group.
  • TJ-NA048 The detected crystal is colorless needle-shaped (0.30 ⁇ 0.04 ⁇ 0.04mm3), belonging to the monoclinic P1 space group.
  • Dc 1.366g/cm3
  • the number of electrons in the unit cell F(000) 620.0
  • the linear absorption coefficient of the unit cell ⁇ (Cu K ⁇ ) 0.856mm–1
  • T 150.00(13)K.
  • Embodiment 3 preparation NAG0052, L96
  • the starting material Compound 1 was purchased from Jiangsu Beida Pharmaceutical Technology Co., Ltd.
  • the synthetic route of compound NAG0052 is as follows:
  • TMSCN (13.5 mL, 101 mmol) was added in one portion to a solution of compound 2 (13.0 g, 33.6 mmol) in DCM (300 mL), followed by dropwise addition of a solution of TMSOTf (9.14 mL, 50.5 mmol) in DCM (30 mL).
  • the reaction solution was stirred at 20°C for 15 hours. After the reaction was completed, the system was quenched with saturated NaHCO aqueous solution (80mL), and extracted with DCM (150mL x 2).
  • the compound NAG0024 (271mg, 0.151mmol) was dissolved in anhydrous THF (2mL) and anhydrous DMF (4mL), and 3A molecular sieves were added, followed by compound 12 (100mg, 0.151mmol), HOBt (25mg, 0.181mmol), DCC (38mg, 0.181mmol) and DIEA (39mg, 0.30mmol) 2 mmol).
  • the reaction solution was reacted at 45°C for 16h. After LC-MS showed that the reaction was complete, it was quenched with water and filtered. After the filtrate was concentrated, it was purified by C18 reverse phase column (H 2 O/MeCN) to obtain compound 13 (210 mg, yield 57%).
  • the compound NAG0052 (157mg, 0.062mmol) containing a carboxylic acid group was dissolved in anhydrous DMF (3mL). After the substrate was completely dissolved, anhydrous acetonitrile (4mL), DIEA (0.03mL, 0.154mmol, 2.5eq) and HBTU (35mg, 0.093mmol, 1.5eq) were added in sequence. After the reaction solution was mixed evenly, macroporous amine methyl resin (476mg, blank load was 0.41mmol/g, target load was 0.1mmol/g) was added. The reaction solution was placed on a shaker (temperature: 25° C., rotation speed: 200 rpm) and shaken overnight. The reaction liquid was filtered, and the filter cake was washed successively with DCM and anhydrous acetonitrile, and the solid was collected and dried overnight in vacuum.
  • the above solid was dispersed in anhydrous acetonitrile (5 mL), and pyridine (0.18 mL), DMAP (3 mg), NMI (0.12 mL) and CapB1 (2.68 mL) were added sequentially.
  • the reaction solution was placed on a shaker (temperature: 25° C., rotation speed: 200 rpm) and shaken for 2 h.
  • the reaction liquid was filtered, and the filter cake was washed with anhydrous acetonitrile, and the solid was collected and vacuum-dried overnight to obtain a resin with a carrier.
  • the loading capacity was determined to be 0.1 mmol/g.
  • NAG0052 For the NAG0052 that has been connected to the resin, use the resin as a starting point, and connect the nucleoside monomers one by one from the 3'-5' direction according to the sequence of nucleotide arrangement. Each connection of a nucleoside monomer includes four steps of deprotection, coupling, capping, oxidation or sulfurization. The operation is conventional in the art.
  • NAG0052 is connected to the sequence through solid-phase synthesis, and after aminolysis, the structure of NAG0052 loses some functional groups to become NAG0052'.
  • the prepared dsRNA had the sense and antisense strands shown in Table 1 and Table 2.
  • uppercase letters G, A, C, and U represent nucleotides containing guanine, adenine, cytosine, and uracil, respectively, lowercase letter m represents 2'-methoxy modification, lowercase letter f represents 2'-fluoro modification, and lowercase letter s represents a phosphorothioate group connection between two nucleotides adjacent to the left and right of the letter s; the same below.
  • Example 5 Inhibition of dsRNA on target gene mRNA expression in vivo
  • mice Male 6-8 week-old C57BL/6 mice were randomly divided into 6 groups, 3 at each time point, and each group was given TRD007205, reference positive TRD002218 and PBS.
  • mice All animals were dosed according to their total body weight, and were administered once by subcutaneous injection.
  • the dose of dsRNA (based on the amount of nucleotide without ligand) was 1 mg/kg, and the volume of administration was 5 mL/kg.
  • the mice were sacrificed, the liver was collected, and stored with RNA later (Sigma Aldrich); then the liver tissue was homogenized with a tissue homogenizer, and then the total RNA of the liver tissue was extracted with a tissue RNA extraction kit (Fanzhi Medical Technology, FG0412) according to the operation steps marked in the operation manual.
  • tissue RNA extraction kit Fanzhi Medical Technology, FG0412
  • the total RNA was reverse-transcribed into cDNA, and the expression of TTR mRNA (transthyretin mRNA) in liver tissue was detected by real-time fluorescent quantitative PCR method.
  • TTR mRNA transthyretin mRNA
  • GPDH glyceraldehyde 3-phosphate dehydrogenase
  • Taqman probe primers for TTR and GAPDH were used to detect the mRNA expression levels of TTR and GAPDH, respectively.
  • TTR mRNA expression was calculated according to the following equation:
  • TTR mRNA expression [(TTR mRNA expression of test group/GAPDH mRNA expression of test group)/(TTR mRNA expression of control group/GAPDH mRNA expression of control group)] ⁇ 100%.
  • each connection of a nucleoside monomer includes four steps of deprotection, coupling, capping, oxidation or sulfurization. Specifically refer to the synthetic method of embodiment 7.
  • the prepared dsRNA had the sense and antisense strands shown in Table 5 and Table 6.
  • (-)hmpNA(C) means
  • NAG0052' The structure of NAG0052' is:
  • Example 7 dsRNA inhibits human AGT in primary human hepatocytes (PHH) - 7 concentration points inhibit activity
  • dsRNA was screened for activity in primary human hepatocytes (PHH) using 7 concentration gradients. Each dsRNA sample was transfected with a constant concentration of 20 nM, 5-fold serial dilution and 7 concentration points.
  • PHL Primary human hepatocytes
  • the primary human hepatocytes (PHH) were resuscitated and inoculated in a 96-well plate at a seeding density of 3 ⁇ 10 cells per well and 80 ⁇ L of medium per well.
  • Lipofectamine RNAi MAX (ThermoFisher, 13778150) to transfect dsRNA, and the gradient final concentration of dsRNA transfection is 10nM, 2nM, 0.4nM, 0.08nM, 0.016nM, 0.0032nM and 0.00064nM.
  • RNA reverse transcription experiment (Takara PrimeScript TM II 1st Strand cDNA Synthesis Kit (6210A) and quantitative real-time PCR (Takara PrimeScript TM II 1st Strand cDNA Synthesis Kit (621 OA) detection, measuring the mRNA level of human AGT, and correcting the mRNA level of human AGT according to the level of GAPDH internal reference gene.
  • Inhibition rate (%) (1-remaining amount of target gene expression)*100%.
  • Results are expressed as percent remaining human AGT mRNA expression relative to control dsRNA-treated cells. See Table 11 for the IC50 results of the inhibition rate.
  • Example 8 Multi-concentration point inhibitory activity against AGT in human liver cancer cell line (Hep3B)
  • Dose-response experiments were performed in a human hepatoma cell line (Hep3B) using a 7 concentration gradient.
  • Hep3B cells were seeded in a 96-well plate at about 20,000 cells/well, with 100 ⁇ L of medium per well.
  • transfection refer to the product instruction manual, use Lipofectamine RNAi MAX (ThermoFisher, 13778150) to transfect the sample, and the gradient final concentration of sample transfection is 10, 2, 0.4, 0.08, 0.016, 0.0032 and 0.00064nM.
  • RNA reverse transcription experiments Takara PrimeScript TM II 1st Strand cDNA Synthesis Kit (6210A) and quantitative real-time PCR (Takara PrimeScript TM II 1st Strand cDNA Synthesis Kit (6210A) detects and measures the human mRNA level, and corrects the human AGT mRNA level according to the GAPDH internal reference gene level.
  • Example 9 Inhibition of AGT in human liver cancer cell line (Hep3B) - multi-concentration point inhibitory activity
  • Dose-response experiments were performed in a human hepatoma cell line (Hep3B) using a 7 concentration gradient.
  • Hep3B cells were seeded in a 96-well plate at about 20,000 cells/well, with 100 ⁇ L of medium per well.
  • transfection refer to the product instruction manual, use Lipofectamine RNAi MAX (ThermoFisher, 13778150) to transfect samples, and the gradient final concentration of sample transfection is 10, 2, 0.4, 0.08, 0.016, 0.0032 and 0.00064nM.
  • the high-throughput cellular RNA extraction kit was used for total cellular RNA extraction, RNA reverse transcription experiments, and quantitative real-time PCR detection to measure the human mRNA level, and correct the human AGT mRNA level according to the GAPDH internal reference gene level.
  • TJR100283 The inhibitory activity of TJR100283 on AGT is better than that of TJR100286, TJR100290, TJR100291, TJR100292 and TJR100293.
  • the sequences of these samples were transformed by the first base mutation at the 5' end of the TJR100283 sequence, and the left and right base shifts.
  • the results showed that TJR100283 exhibited better inhibitory activity on AGT, and any base change weakened the inhibitory activity on AGT.
  • Embodiment 10 To the inhibition of AGT in the monkey primary hepatocyte (PCH) - multi-concentration point inhibitory activity
  • RNAiMAX Lipofectamine RNAiMAX (ThermoFisher, 13778150) to transfect the sample, and the gradient final concentration of sample transfection is 10, 2, 0.4, 0.08, 0.016, 0.0032 and 0.00064nM.
  • the expression level of target AGT mRNA in each sample was calculated by ⁇ Ct relative quantification method.
  • the relative expression of the target gene is represented by 2 - ⁇ CT , and the calculation formula is as follows:
  • ⁇ CT the average Ct value of the target gene - the average Ct value of the internal reference gene
  • ⁇ CT ⁇ CT (dosing group) group- ⁇ CT (control group);
  • IC50 was calculated using GraphPad Prism software (four parameter logistic equations). The results are shown in Table 15.
  • TJR100283 was significantly better than that of TJR100292, TJR100293 and TJR100295. It shows that the TJR100283 sequence itself has a strong inhibitory activity on AGT.

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Abstract

L'invention concerne un ARNdb chimiquement modifié pour inhiber l'expression de l'angiotensinogène (AGT) et son procédé de préparation. L'invention concerne en outre une composition pharmaceutique, un vecteur, une cellule et un kit contenant l'ARNdb, et leur utilisation dans la préparation d'un médicament pour la prévention et/ou le traitement de l'hypertension.
PCT/CN2023/073189 2022-01-20 2023-01-19 Arn double brin, son utilisation et son procédé de préparation WO2023138663A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
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