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WO2023169335A1 - Composé de ciblage d'arnm-acide gras, procédé de préparation associé et application associée - Google Patents

Composé de ciblage d'arnm-acide gras, procédé de préparation associé et application associée Download PDF

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Publication number
WO2023169335A1
WO2023169335A1 PCT/CN2023/079617 CN2023079617W WO2023169335A1 WO 2023169335 A1 WO2023169335 A1 WO 2023169335A1 CN 2023079617 W CN2023079617 W CN 2023079617W WO 2023169335 A1 WO2023169335 A1 WO 2023169335A1
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mrna
fatty acid
formula
compound
preparation
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Chinese (zh)
Inventor
胡勇
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Wuhan Rhegen Biotechnology Co Ltd
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Wuhan Rhegen Biotechnology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • 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
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/505—Erythropoietin [EPO]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
    • C12N9/0044—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on other nitrogen compounds as donors (1.7)
    • C12N9/0046—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on other nitrogen compounds as donors (1.7) with oxygen as acceptor (1.7.3)
    • C12N9/0048—Uricase (1.7.3.3)
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0069—Oxidoreductases (1.) acting on single donors with incorporation of molecular oxygen, i.e. oxygenases (1.13)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y107/00—Oxidoreductases acting on other nitrogenous compounds as donors (1.7)
    • C12Y107/03—Oxidoreductases acting on other nitrogenous compounds as donors (1.7) with oxygen as acceptor (1.7.3)
    • C12Y107/03003—Factor-independent urate hydroxylase (1.7.3.3), i.e. uricase

Definitions

  • the present invention relates to the field of genetic engineering technology, and in particular to an mRNA-fatty acid targeting compound and its preparation method and application.
  • Nucleic acid-based therapy is a unique treatment approach.
  • the therapeutic effects of traditional therapies are often short-lived because they tend to target proteins rather than the underlying genetic problem.
  • nucleic acid therapies can achieve long-term effects through gene suppression, addition, replacement or editing.
  • the delivery of mRNA into specific tissue cells can be achieved through different methods, such as lipid nanoparticles, GalNac, etc., but these methods cannot be specifically delivered to muscle cells.
  • Skeletal and cardiac muscle cells rely heavily on the oxidation of long-chain fatty acids for contraction.
  • Fatty acids are transported to muscle tissue through the blood complexed with albumin or covalently bound to triacylglycerols, forming a neutral lipid core of circulating triglyceride-rich lipoproteins (such as chylomicrons or very low-density lipoproteins).
  • the capillary endothelium is the first barrier for fatty acids from the vascular compartment to reach bone and cardiomyocytes.
  • the mechanisms of fatty acid movement across membranes are not fully understood, but recent studies suggest that interaction of albumin-fatty acid complexes with endothelial membranes may promote fatty acid uptake.
  • Serum albumin is an endogenous fatty acid transporter.
  • Albumin the most abundant plasma protein in human blood, is synthesized in the liver and released into the lumen of blood vessels.
  • Albumin interacts with multiple cellular receptors, such as the glycoproteins Gp60, Gp30, and Gp18a, the Megalin/Cubilin complex, and the neonatal Fc receptor (FcRn). Interactions with these receptors enable albumin recycling, pinocytosis, and extended half-life.
  • Albumin contains multiple hydrophobic vesicles that can bind fatty acids and steroids as well as different drugs.
  • cholesterol-binding oligonucleotides can achieve siRNA delivery through low-density lipoprotein receptor-mediated endocytosis.
  • Wolfrum et al. conjugated cholesterol and various lipids to siRNA and demonstrated that long-chain fatty acids and cholesterol can facilitate siRNA entry into cells, resulting in efficient gene silencing in mice.
  • This group of studies also demonstrates that efficient and selective uptake of siRNA conjugates relies on interactions between lipoprotein particles, lipoprotein receptors, and other cell surface receptors.
  • fatty acid-conjugated siRNA has achieved efficient muscle cell-targeted drug delivery.
  • fatty acid-conjugated siRNA has been discovered for many years, its messenger RNA (mRNA) muscle delivery system has not been able to achieve a breakthrough.
  • mRNA messenger RNA
  • the existing technology cannot achieve the coupling of fatty acids and mRNA, and mRNA- Advances in muscle cell-targeted therapies have been hampered by the inefficiency of fatty acid complexes when delivered in vivo.
  • the present invention provides an mRNA-fatty acid targeting compound and its preparation method and application.
  • the targeting compound provided by the invention can achieve efficient coupling of fatty acids and mRNA, and has good muscle targeted delivery effect.
  • R in formula I is -C n H 2n+1 or -C n H 2n-1 , where n represents the number of carbon atoms;
  • the value of n ranges from 15 to 22.
  • the mRNA is an mRNA encoding a functional protein.
  • the invention also provides a method for preparing the mRNA-fatty acid targeting compound described in the above scheme, which includes the following steps:
  • R is -C n H 2n+1 or -C n H 2n-1 , n represents the number of carbon atoms, and A represents adenylate.
  • the preparation method of the oligoadenylate-fatty acid compound having the structure shown in formula b includes the following steps:
  • the compound having the structure shown in formula a and oligoadenylic acid are mixed for a condensation reaction to obtain the oligoadenylic acid-fatty acid compound having the structure shown in formula b; the structural formula of the oligoadenylic acid is as shown in formula c Show;
  • the temperature of the condensation reaction is room temperature and the time is 8 to 15 hours.
  • the preparation method of the compound having the structure shown in formula a includes the following steps:
  • the fatty acid, pentafluorophenyl trifluoroacetate and an alkaline reagent are mixed to perform a transesterification reaction to obtain a compound having the structure shown in formula a; the structural formula of the fatty acid is expressed as R-COOH.
  • the temperature of the transesterification reaction is room temperature and the time is 0.5 to 2 hours.
  • the system components of the RNA ligation reaction include: Tris-HCl buffer, MgCl 2 , PEG 8000, RNA ligase, adenosine triphosphate, target mRNA and oligoadenylate-fatty acid compound.
  • the present invention also provides the application of the mRNA-fatty acid targeting compound described in the above scheme or the mRNA-fatty acid targeting compound prepared by the preparation method described in the above scheme in the preparation of protein replacement drugs and metabolic disease treatment drugs.
  • the dosage forms of the protein replacement drugs and metabolic disease treatment drugs are injections.
  • the invention provides an mRNA-fatty acid targeting compound, the general structural formula of which is shown in Formula I.
  • the present invention provides a brand new mRNA-fatty acid targeting compound, which connects the fatty acid group to the amino group of adenine at the 3' end of the mRNA, solving the problem that fatty acids cannot be efficiently coupled to the mRNA, and the mRNA-fatty acid targeting compound
  • the encoded target protein has high specific expression in muscle tissue and can be directly delivered to muscle cells via intramuscular injection or systemic injection.
  • the present invention also provides a method for preparing the mRNA-fatty acid targeting compound described in the above scheme.
  • the present invention utilizes target mRNA and oligoadenylate-fatty acid compound to perform RNA ligation reaction to obtain the mRNA-fatty acid targeting compound of the present invention, and prepares The steps are simple and easy to operate.
  • Figure 1 is the quantitative results of mRNA in mouse liver in Example 2;
  • Figure 2 is the quantitative results of mRNA in mouse quadriceps muscle in Example 2;
  • Figure 3 shows the expression level test results of the target protein encoded by mRNA-palmitic acid in different tissues in Example 3;
  • Figure 4 shows the expression level test results of the target protein encoded by mRNA-oleic acid in different tissues in Example 5;
  • Figure 5 shows the expression level of the target protein encoded by mRNA-oleic acid in mice and the blood sugar reduction test results in Example 6;
  • Figure 6 shows the uric acid reduction test results in mice of the target protein encoded by mRNA-oleic acid in Example 7.
  • the invention provides an mRNA-fatty acid targeting compound, the general structural formula of which is shown in formula I:
  • R in formula I is -C n H 2n+1 or -C n H 2n-1 , where n represents the number of carbon atoms; represents mRNA.
  • n 15-22, preferably 16-21.
  • the mRNA-fatty acid targeting compound is an mRNA-palmitic acid targeting compound, and its structural formula is as shown in Formula I-1:
  • the mRNA-fatty acid targeting compound is an mRNA-oleic acid targeting compound, and the structural formula is as shown in Formula I-2:
  • the mRNA is an mRNA that can encode a functional protein.
  • the present invention has no special requirements for the specific sequence of the mRNA. It can be selected according to the sequence of the target gene; in specific embodiments of the present invention, the mRNA Preferably it is hEPO mRNA, LUC mRNA, hGLP1 mRNA or hRAS mRNA.
  • the invention also provides a method for preparing the mRNA-fatty acid targeting compound described in the above scheme, which includes the following steps:
  • R is -C n H 2n+1 or -C n H 2n-1 , n represents the number of carbon atoms, and A represents adenylate.
  • the preparation method of the oligoadenylate-fatty acid compound having the structure shown in formula b includes the following steps:
  • the compound having the structure shown in formula a and oligoadenylic acid are mixed for a condensation reaction to obtain the oligoadenylic acid-fatty acid compound having the structure shown in formula b; the structural formula of the oligoadenylic acid is as shown in formula c Show;
  • the preparation method of the compound having the structure shown in formula a includes the following steps:
  • the fatty acid, pentafluorophenyl trifluoroacetate and an alkaline reagent are mixed to perform a transesterification reaction to obtain a compound having the structure shown in formula a; the structural formula of the fatty acid is expressed as R-COOH.
  • fatty acids, pentafluorophenyl trifluoroacetate and alkaline reagents are mixed to perform a transesterification reaction to obtain a compound having a structure represented by formula a.
  • the fatty acid is preferably palmitic acid or oleic acid.
  • the alkaline reagent is preferably triethylamine, which provides a suitable alkaline environment for the transesterification reaction to proceed.
  • the mass ratio of the fatty acid and pentafluorophenyl trifluoroacetate is preferably 0.2:2 to 0.4:1; the dosage ratio of the fatty acid to triethylamine is preferably 0.2 to 0.4g.
  • the pH value of the transesterification reaction at 8 to 10 by controlling the amount of triethylamine; the transesterification reaction is carried out in a solvent; the transesterification reaction is carried out with
  • the solvent is preferably dichloromethane, chloroform or benzene; the present invention has no special requirements on the amount of the solvent, as long as it can dissolve the raw materials and make the reaction proceed smoothly.
  • the temperature of the transesterification reaction is room temperature and the time is 0.5 to 2 hours.
  • the present invention preferably dilutes, washes and separates the obtained product liquid in sequence, and sequentially dries, filters and concentrates the obtained organic layer to obtain a crude product, which is then purified by silica gel column chromatography. A compound having the structure shown in formula a is obtained.
  • the diluting solvent is preferably the same as the transesterification solvent; the washing is preferably using sodium bicarbonate solution and sodium bisulfate solution in sequence; the concentration of the sodium bicarbonate solution is preferably 5 mmol/L , the concentration of the sodium bisulfate solution is preferably 5mmol/L; the desiccant for drying is preferably anhydrous sodium sulfate, and the desiccant is removed by filtration after drying; the eluent for silica gel column chromatography purification is preferably chloroform ; In the present invention, it is preferred to mix chloroform and silica gel into a homogenate, then pack the column, and then dissolve the crude product and put it on the column for purification; the method for dissolving the crude product is preferably: dissolving the crude product in dimethyl sulfoxide , and then add acetonitrile and triethylamine to obtain a crude product solution; the concentration of acetonitrile in the crude product solution
  • the present invention mixes the compound with the structure shown in formula a and oligoadenylate to perform a condensation reaction to obtain the oligoadenylate-fatty acid compound with the structure shown in formula b ( Denoted as oligo(A)-fatty acid).
  • the temperature of the condensation reaction is preferably room temperature, and the time is preferably 8 to 15 hours;
  • the solvent for the condensation reaction is preferably sodium tetraborate solution, and the concentration of the sodium tetraborate solution is preferably 0.5 to 2 mol/L.
  • the structural formula of the oligoadenylate is as shown in formula c (see above for specific structural formula), and the number of adenylate in the oligoadenylate is preferably 6 to 10; so
  • the molar ratio of the compound having the structure represented by formula a and oligoadenylic acid is preferably 5:1 to 1:1, more preferably 4:1 to 3:1.
  • the present invention has no special requirements on the source of the oligoadenylate, and it can be synthesized by commercially available products or solid-phase synthesis methods well known in the art.
  • the oligoadenylate Acid was purchased from Sangon Bioengineering (Shanghai) Co., Ltd. or Suzhou Jinweizhi Biotechnology Co., Ltd.
  • the present invention preferably dilutes the reaction product obtained with enzyme-free water, and then performs HPLC purification using an ion exchange column to obtain the oligoadenylate-fatty acid compound having the structure represented by formula b.
  • the present invention performs an RNA ligation reaction between the oligoadenylate-fatty acid compound and target mRNA under the catalysis of RNA ligase to obtain formula I.
  • the system composition of the RNA ligation reaction preferably includes: Tris-HCl buffer, MgCl 2 , PEG 8000, T4 RNA Ligase 1, adenosine triphosphate (ATP), target mRNA and oligoadenylate-fatty acid compound;
  • the RNA ligase is preferably T4 RNA Ligase 1.
  • the pH value of the Tris-HCl buffer is preferably 7 to 7.5, more preferably 7.5, and the RNA
  • the concentration of MgCl 2 is preferably 0.1 to 1 mmol/L
  • the concentration of PEG-8000 is preferably 5 to 50 mg/mL
  • the concentration of T4 RNA Ligase 1 is preferably 15 to 25 U, and more preferably 20 U
  • ATP The concentration is preferably 0.5 ⁇ 2.5mmol/L, more preferably 1mmol/L
  • the molar ratio of the target mRNA and oligoadenylate-fatty acid compound is preferably 1:50 ⁇ 50:1, more preferably 1:20 ⁇ 20:1, most preferably 1:2
  • the MgCl 2 and PEG 8000 are used to maintain enzyme activity
  • ATP is used as the enzymatic reaction substrate of T4 RNA Ligase 1 and is added between the two nucleic acid sequences. .
  • all components are preferably 0.1 to 1 mmol/L
  • the temperature of the RNA ligation reaction is preferably 16-25°C, and the reaction time is preferably 30min-32h; in specific embodiments of the invention, when the temperature of the RNA ligation reaction is 16°C, the reaction The time is preferably 2 to 32 hours; when the temperature of the RNA ligation reaction is 25°C, the reaction time is preferably 30 min to 16 hours.
  • the present invention preferably purifies the product liquid to obtain the mRNA-fatty acid targeting compound; the present invention has no special requirements for the purification method, and can adopt methods well known to those skilled in the art, such as layer analysis method, liquid chromatography, lithium chloride precipitation method, phenol chloroform extraction method, ethanol precipitation method or ammonium acetate precipitation method.
  • the lithium chloride precipitation method is preferably used.
  • the lithium precipitation method specifically includes: adding lithium chloride solution into the product liquid until the concentration of lithium chloride in the liquid is 0.5 mol/L, so that the mRNA-fatty acid targeting compound is precipitated.
  • the present invention also provides the application of the mRNA-fatty acid targeting compound described in the above scheme or the mRNA-fatty acid targeting compound prepared by the preparation method described in the above scheme in the preparation of protein replacement drugs and metabolic disease treatment drugs; in the present invention,
  • the dosage forms of the protein replacement drugs and metabolic disease treatment drugs are preferably injections, and the administration route of the injections is preferably intramuscular injection; the target protein encoded by the mRNA-fatty acid targeting compound provided by the invention is specifically expressed in muscle tissue. High, it can be delivered directly to muscle cells through systemic circulation injection, and has broad application prospects in intramuscular injection vaccines.
  • the coding region sequence of hEPO mRNA used in the examples is:
  • the coding region sequence of LUC mRNA used in the examples is:
  • the coding region sequence of hGLP1 mRNA used in the examples is:
  • the coding region sequence of hRAS mRNA used in the examples is:
  • a Dissolve the crude product in DMSO, add acetonitrile and triethylamine to obtain a crude product solution, in which the concentration of the crude product is 40mmol/L, the concentration of acetonitrile is 20mmol/L, and the concentration of triethylamine is 16mmol/L;
  • aqueous phase Dilute LUC mRNA in citric acid buffer at a final concentration of 2 ⁇ g/ ⁇ l to obtain an mRNA buffer; prepare an ethanol phase solution according to Table 1;
  • phase A mRNA buffer
  • phase B ethanol phase solution
  • mice (purchased from Beijing Vitong Lever) aged 6 to 8 weeks were raised under SPF conditions and kept in cages with a 12-hour light and 12-hour dark cycle, and were treated with Luc mRNA-palmitic acid targeting compounds. and LNP-LUC mRNA were injected into the tail vein of mice respectively. The injection doses were 1 mg, 5 mg, 10 mg, and 15 mg respectively. After 24 hours, the liver and quadriceps muscles of the mice were taken, and the mRNA was extracted using a tissue RNA extraction kit for fluorescence quantification. PCR to quantify target mRNA in different tissues. The experimental results are shown in Figures 1-2.
  • Example 2 Other conditions were the same as Example 1, except that LUC mRNA was replaced with hEPO mRNA to obtain hEPO mRNA-palmitic acid targeting compound.
  • Example 4 Other conditions were the same as in Example 4, except that hEPO mRNA was replaced with hGLP1 mRNA to obtain hGLP1 mRNA-oleic acid targeting compound.
  • mRNA-oleic acid encodes exocrine urate oxidase and is specifically expressed in muscle tissue:
  • BKS db/db hyperglycemia model mice (purchased from Beijing Vitong Lever) aged 6-8 weeks were raised under SPF conditions and kept in cages with a 12-hour light and 12-hour dark cycle.
  • hGLP1 mRNA-oil Acid-targeting compounds were injected intramuscularly into mice at a dose of 5 mg. After 24 hours, the serum was taken, the total protein was extracted, and the blood glucose concentration of the mice was quantified by a blood glucose meter. At the same time, the total protein and blood glucose of the mice in the blank control group were measured. Concentration is quantified.
  • the experimental results are shown in Figure 5. The left side of Figure 5 shows the expression of GLP-1, and the right side shows the blood glucose concentration.
  • the experimental group in Figure 5 is the experimental group injected with hGLP1 mRNA-oleic acid targeting compound. According to Figure 5, it can be seen that the experimental group injected with hGLP1 mRNA-oleic acid targeting compound expressed high expression of the target protein product and significantly reduced blood glucose concentration.
  • Example 4 Other conditions were the same as in Example 4, except that hEPO mRNA was replaced with hRAS mRNA to obtain hRAS mRNA-oleic acid targeting compound.
  • mRNA-oleic acid encodes exocrine urate oxidase and is specifically expressed in muscle tissue:

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Abstract

L'invention concerne un composé de ciblage d'ARNm-acide gras, un procédé de préparation associé et une application associée, se rapportant au domaine technique de l'ingénierie génétique. Une réaction de ligature d'ARN d'un composé d'acide gras d'oligoadénylate et d'un ARNm cible est effectuée pour obtenir le composé de ciblage d'ARNm-acide gras. L'invention concerne un nouveau composé de ciblage d'ARNm-acide gras. Le problème selon lequel un acide gras ne peut pas être couplé efficacement à un ARNm est résolu ; de plus, la quantité d'expression spécifique d'une protéine cible codée du composé de ciblage d'ARNm-acide gras dans un tissu musculaire est élevée, de telle sorte qu'une administration directe à des cellules musculaires au moyen d'une injection intramusculaire ou d'une injection dans la circulation systémique peut être effectuée.
PCT/CN2023/079617 2022-03-05 2023-03-03 Composé de ciblage d'arnm-acide gras, procédé de préparation associé et application associée Ceased WO2023169335A1 (fr)

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CN114685586B (zh) * 2022-03-05 2025-07-18 武汉瑞佶生物科技有限公司 一种mRNA-脂肪酸靶向化合物及其制备方法和应用

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