90 results about "Acetylgalactosamine" patented technology

The disclosure provides methods for synthesis of peracetylgalactosamine-1-pentanoic acid, also called peracetylated D-galactosamine C5 linker or GalNAc C5 linker, using a vegetal source as a starting material, such as vegetal-sourced D-glucosamine or D-glucosamine hydrochloride. Also provided are methods for purifying the peracetylgalactosamine-1-pentanoic acid, or GalNAc C5 linker, thus produced so that the end product comprises fewer impurities.

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents such as small interfering RNA (siRNA) molecules, able to inhibit proprotein convertase subtilisin kexin 9 (PCSK9) gene expression. Also disclosed are pharmaceutical compositions that include PCSK9 RNAi agents and methods of use thereof. The PCSK9 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that comprise N-acetyl-galactosamine, to facilitate the delivery to hepatocyte cells. Delivery of the PCSK9 RNAi agents in vivo provides for in vivo provides for inhibition of PCSK9 gene expression and thereby reduction of PCSK9 protein. The RNAi agents can be used in methods of treatment of diseases or disorders mediated at least in part by PCSK9 gene expression, including among others hypercholesterolemia, familial hypercholesterolemia including heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH), familial hypobetalipoproteinemia, hyperlipidemia, coronary artery disease, polygenic dyslipidemia, heart disease, cardiovascular disease (CVD) including clinical atherosclerotic cardiovascular disease (ASCVD).

Embodiments of the present application relate to functionalized N-acetylgalactosamine-analogs, methods of making, and uses of the same. In particular, mono or trivalent N-acetylgalactosamine analogs may be prepared by utilizing a wide variety of linkers containing functional groups. These functionalized N-acetylgalactosamine-analogs may be used in the preparation of targeted delivery of oligonucleotide-based therapeutics.

The application discloses a preparation method of a liver-targeting drug delivery carrier, and comprises the following steps: synthesizing bromic acid N-acetylgalactosamine ester; and synthesizing the liver-targeting drug delivery carrier. x The liver-targeting drug delivery carrier GalNAc-C x CD is designed based on bromic acid N-acetylgalactosamine ester Br-C GalNAc and beta-cyclodextrin, which can include poorly soluble drugs to be delivered to the liver and released in a targeted manner, greatly improves the targeting efficiency on the liver, and the targeting delivery rate can reach more than 70%, while effectively improving the solubility and bioavailability of the poorly soluble drugs, improving the drug treatment effect, providing a new strategy for the delivery of other poorly soluble drugs for treating liver diseases, and laying a foundation for the development of drugs and functional foods for intervening NASH.

The present disclosure provides a combination comprising an antibody that specifically binds to C5 and a C5 iRNA, which is a glycoconjugate containing a ligand with a terminal N-acetylgalactosamine (GalNAc) residue and / or N-acetylglucosamine (GlcNAc) residue. A method for reducing degradation of glycoconjugate RNA by the beta-hexosaminidase enzyme is also provided. The present disclosure also includes a method for treating or preventing a C5-related disease or disorder by administering one or more doses of an anti-C5 antibody or antigen-binding fragment thereof in combination with one or more doses of a C5 iRNA; preferably, the anti-C5 antibody or fragment and the C5 iRNA are in a combination. The present disclosure also includes a dosing regimen for treating a C5-related disease or disorder with a combination of an anti-C5 antibody and a C5 iRNA in either a treatment-naive subject or a subject switching from a previous C5 inhibitor therapy.

The current invention concerns methods for the synthesis of 6-azido-6-deoxy-2-N-acetyl-monosaccharide-nucleoside diphosphate, in particular 6-azido-6-deoxy-2-N-acetyl-D-galactosamine-nucleoside diphosphate or 6-azido-6-deoxy-2-N-acetyl-D-glucosamine-nucleoside diphosphate. The synthesis method according to the invention is characterized by being highly efficient and high yielding. Also part of the present invention are key intermediates of this process.

This invention belongs to the field of biochemical analysis technology, and discloses a magnetic bead for enriching tyrosine N-acetylgalactosamine modification sites, its preparation method, and its application. Specifically, it discloses a recombinant antibody, including the Fab fragment of a G10C antibody, the Fc region of an immunoglobulin, and an AviTag tag. This invention provides a recombinant antibody capable of specifically targeting and enriching tyrosine-O-GalNAc glycosylated peptides. By coupling this recombinant antibody to magnetic beads, the enrichment of tyrosine-O-GalNAc glycosylated peptides can be effectively improved, and interference and signal masking by glycosylation modifications on serine and threonine can be avoided, enabling the identification of more tyrosine glycosylation sites in a single sample.

This disclosure relates to RNAi agents capable of inhibiting complement factor B (CFB) gene expression. Pharmaceutical compositions containing CFB RNAi agents and methods of use thereof are also disclosed. The CFB RNAi agents disclosed herein may be conjugated to a targeted ligand containing an N-acetyl-galactosamine ligand to facilitate in vivo delivery to hepatocytes. RNAi agents can be used in methods of treating diseases, disorders, or conditions partially mediated by CFB gene expression, including IgA nephropathy (IgAN), C3 glomerulopathy (C3G), immune complex-mediated membrane proliferative glomerulonephritis (IC-MPGN), lupus nephritis (LN), anti-glomerular basement membrane antibody disease (anti-GBM), ischemia-reperfusion injury and T-cell-mediated rejection in kidney transplantation (TCMR), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, age-related macular degeneration (AMD) including early and / or intermediate-stage AMD, geographic atrophy (GA), glaucoma, Doyne honeycomb retinal dystrophy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), pre-eclampsia, rheumatoid arthritis (RA), and / or other complement-mediated disorders.

The present disclosure relates to RNAi agents, e.g., double-stranded RNAi agents, capable of inhibiting the expression of a mitochondrial amidoxime reducing component 1 (MARC1) gene. Also disclosed are pharmaceutical compositions comprising the MARC1 RNAi agent and methods of using the same. In some embodiments, the MARC1 RNAi agents disclosed herein can be conjugated to targeting ligands, including ligands comprising N-acetyl-galactosamine, to facilitate delivery to hepatocytes. Delivery of the MARC1 RNAi agent in vivo provides inhibition of MARC1 gene expression. RNAi agents may be used in methods of treating diseases, disorders or conditions mediated in part by MARC1 gene expression, including non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, autoimmune hepatitis, hepatic fibrosis, cirrhosis, elevated blood cholesterol levels, hypertriglyceridemia, liver disease, and / or other MARC1 related diseases.

The present disclosure relates to RNAi agents able to inhibit Complement Factor B (CFB) gene expression. Also disclosed are pharmaceutical compositions that include CFB RNAi agents and methods of use thereof. The CFB RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that comprise N-acetyl-galactosamine, to facilitate the in vivo delivery to hepatocyte cells. The RNAi agents can be used in methods of treatment of diseases, disorders, or symptoms mediated in part by CFB gene expression, including IgA nephropathy (IgAN), C3 glomerulopathy (C3G), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), lupus nephritis (LN), Anti-Glomerular Basement Membrane disease (anti-GBM), ischemia reperfusion injury and T-cell mediated rejection (TCMR) in kidney transplantation, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, age-related macular degeneration (AMD), including early and / or intermediate AMD, geographic atrophy (GA), glaucoma, Doyne honeycomb retinal dystrophy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), pre-eclampsia, rheumatoid arthritis (RA), and / or other complement-mediated diseases.

The present invention relates to compositions and methods for regulating apolipoprotein (a) expression. Specifically, oligomeric compounds with conjugate groups targeting apolipoprotein (a) [apo (a)] are provided herein. In certain embodiments, the oligomeric compound targeting apo (a) is conjugated to N-acetylgalactosamine. Also disclosed herein are conjugated oligomeric compounds targeting apo (a) for reducing apo (a) to treat, prevent or improve diseases, conditions or symptoms associated with apo (a) and / or Lp (a). Certain diseases, conditions or symptoms associated with apo (a) and / or Lp (a) include inflammatory, cardiovascular and / or metabolic diseases, conditions or symptoms. The conjugated oligomeric compounds disclosed herein can be used to treat the diseases, conditions or symptoms in individuals in need thereof.

The invention discloses a preparation method and application of a hepatic parenchymal cell targeting gene delivery system, and relates to construction and preparation of a hepatic parenchymal cell targeting lipid material GalNAc-PEG2000-DSPE modified MKK4-siRNA (siMKK4) loaded lipid nanoparticle gene delivery system GalNAc-LNP-siMKK4, and the hepatic parenchymal cell targeting gene delivery system can be used for active targeting gene therapy of hepatic failure. The parenchymal hepatic cell targeted gene delivery system selects siMKK4 as a liver regeneration promoting gene therapy drug, has the advantages of clear target spot and capability of accurately silencing a target gene, and can protect siMKK4 from being degraded by extracellular nuclease as a gene delivery carrier, so that the targeted gene delivery system has a good application prospect. N-acetylgalactosamine (GalNAc) is selected as a target head, so that therapeutic genes can be precisely targeted and delivered to parenchymal hepatic cells, the risk of tumorigenesis of other parts of an organism can be reduced while liver regeneration is promoted, and a new thought and a new method are provided for liver regeneration treatment of hepatic failure patients.

The present invention relates to a novel compound and application thereof in the inhibition of HBV gene expression. The structure of the compound comprises an interfering nucleic acid for inhibiting HBV gene expression, transition points, and delivery chains of the interfering nucleic acid. By means of the delivery chains, two or three N-acetylgalactosamines can be introduced to an antisense strand 3′ end of such siRNA, and two or one N-acetylgalactosamine can be correspondingly introduced to a sense strand 5′ end, the total number of the introduced N-acetylgalactosamines being four. In vitro and in vivo pharmacological experiments prove that such a novel compound can continuously and efficiently inhibit HBV gene expression.

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit Yellow Fever Virus (YFV) viral genome expression. Also disclosed are pharmaceutical compositions that include YFV RNAi agents and methods of use thereof. The YFV RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that comprise N-acetyl-galactosamine, to facilitate the delivery to hepatocyte cells. Delivery of the YFV RNAi agents in vivo provides for inhibition of YFV viral genome expression. The RNAi agents can be used in methods of treatment of diseases, disorders, or symptoms caused by YFV infection, such as liver failure.

The invention provides a novel FAPI trimer compound based on a GalNAc (N-acetylgalactosamine) link chain, a preparation method of the FAPI trimer compound, a developing agent based on the FAPI trimer compound and a preparation method of a developing agent. The trimerization structure in the FAPI trimer compound molecule provided by the invention can improve the in-vivo dynamic characteristics of the compound and prolong the residence time of the compound in tumors; the imaging agent based on the FAPI trimer compound can improve the uptake and imaging effects in tumors, and has good application prospects in PET / SPECT imaging, preparation of drugs for diagnosing tumors expressed by FAP-q and drugs for marking therapeutic nuclide (177Lu or 90Y) to treat tumors expressed by FAP-q in the future.

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

We provide a technology that can activate NRF2. [Solution] An NRF2 activator comprising one or more chondroitin sulfate oligosaccharides selected from (a) to (c) below as an active ingredient: (a) a disaccharide having a chondroitin sulfate structure (a disaccharide of CS), (b) a trisaccharide having two N-acetyl-D-galactosamine residues and a chondroitin sulfate structure (a trisaccharide of CS having two GalNac residues), (c) a tetrasaccharide having a chondroitin sulfate structure (a tetrasaccharide of CS). According to the present invention, NRF2 can be activated. This is expected to promote homeostatic reactions in the body, such as antioxidant reactions, anti-inflammatory reactions, and detoxification reactions, and contribute to maintaining and improving health. It is also expected to contribute to the prevention and improvement of various unhealthy conditions and diseases caused by oxidative stress, inflammation, and toxic chemicals.

Disclosed is a method for preparing an N-acetyl-D-galactosamine tripolymer precursor. In the preparation of the tripolymer precursor, a compound 4 is prepared by the following steps: adding a compound 3, a 4 Å molecular sieve powder, and a reaction solvent into a reactor; inflating and changing protective gas for 3 times; stirring; firstly adding an enol, followed by slowly dropping trimethylsilyl trifluoromethanesulfonate; after a reaction, quenching the reaction with an alkali solution; and performing extraction, separating liquid, washing, drying, filtration, etc., so as to obtain the compound 4. According to the present disclosure, the problems of various production processes, more times of column chromatography for purification of products accompanied by lower yields in the prior art are solved.

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, capable of inhibiting Apolipoprotein C-III (also called APOC3, apoC-III, APOC-III, and APO C-III) gene expression, and compositions that include APOC3 RNAi agents. The APOC3 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that include N-acetyl-galactosamine, to facilitate the delivery to cells, including to hepatocytes. Pharmaceutical compositions that include one or more APOC3 RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the APOC3 RNAi agents in vivo provides for inhibition of APOC3 gene expression, and can result in lower triglycerides and / or cholesterol levels in the subject. The APOC3 RNAi agents can be used in methods of treatment of APOC3-related diseases and disorders, including hypertriglyceridemia, cardiovascular disease, and other metabolic-related disorders and diseases.

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

The invention relates to the technical field of medicines, and discloses synthesis and application of an N-acetylgalactosamine (GalNAc) chemotherapeutic drug conjugate. The invention synthesizes two GalNAc chemotherapeutic drug conjugates, namely (GalNAc) 3-CPT (compound 17) and (GalNAc) 3-Pt-YC (compound 27), the synthesis steps are elaborated in detail, and the performance of the GalNAc chemotherapeutic drug conjugates is researched through various experiments. The cytotoxicity detection shows that the cytotoxicity of the CPT is reduced by the (GalNAc) 3-CPT, and the cytotoxicity of the cis-platinum is improved by the (GalNAc) 3-Pt-YC. In-vivo experiments show that (GalNAc) 3-CPT can significantly improve accumulation of CPT in tumors, the treatment effect of (GalNAc) 3-CPT with different doses is superior to that of CPT, and meanwhile, the toxicity to mice is low. By utilizing GalNAc, the targeting of chemotherapeutic drugs is improved, the toxic and side effects are reduced, the physicochemical properties of the drugs are improved, the problem of drug resistance is expected to be overcome, a more effective method is provided for liver cancer treatment, and the GalNAc has important clinical application potential.

The present disclosure includes methods of treating 05-associated disease or disorder, such as myasthenia gravis, with a combination that includes an antibody or antigen-binding fragment thereof that binds specifically to C5 and a C5 iRNA which is a glycoconjugate that includes a ligand having terminal N-Acetylgalactosamine (GalNAc) residues and / or N-acetylglucosamine (GIcNAc) residues; or with the C5 iRNA monotherapy.

The embodiment of the invention provides a connecting unit for chemical modification of a nucleic acid terminal group, a solid-phase carrier and a preparation method of the solid-phase carrier, the chemical modification comprises N-acetylgalactosamine, and the method comprises the following steps: mixing L-deoxyuridine with iodine, and carrying out iodine substitution reaction to obtain 8-iodine-L-deoxyuridine; carrying out triphenyl methylation on the 8-iodine-L-deoxyuridine to protect 5 '-terminal hydroxyl, carrying out palladium catalytic coupling reaction to obtain 8-alkenyl-L-deoxyuridine ester compounds, and hydrolyzing to obtain unsaturated carboxyl modified L-deoxyuridine derivatives; the unsaturated carboxyl modified L-deoxyuridine derivative and N-acetylgalactosamine are subjected to condensation, and the connecting unit for nucleic acid end group chemical modification is obtained. The connection unit obtained by the method has better enzymolysis resistance, and the synthesis method is simple and efficient.

The present disclosure relates to delivery platforms that specifically and efficiently direct multimeric RNAi agent payloads to hepatocytes in a subject, in vivo. The delivery platforms disclosed herein include metabolically stabilized N-Acetylgalactosamine (NAG or GalNAc) targeting ligands conjugated to two or more RNAi agents, to facilitate the delivery of the oligonucleotide-based payloads to cells, including to hepatocytes. Pharmaceutical compositions that include the metabolically stabilized multimeric RNAi agent conjugate delivery platform are also described, as well as methods of use for the treatment of various diseases and disorders where delivery of a therapeutic payload to a hepatocyte is desirable.

The present disclosure includes methods of treating C5-associated disease or disorder, such as myasthenia gravis, with a combination that includes an antibody or antigen-binding fragment thereof that binds specifically to C5 and a C5 iRNA which is a glycoconjugate that includes a ligand having terminal N-Acetylgalactosamine (GalNAc) residues and / or N-acetylglucosamine (GlcNAc) residues; or with the C5 iRNA monotherapy.

Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.

Provided herein are oligomeric compounds with conjugate groups targeting apoplipoprotein C-III (ApoCIII). In certain embodiments, the ApoCIII targeting oligomeric compounds are conjugated to N-Acetylgalactosamine. Also disclosed herein are conjugated oligomeric compounds targeting ApoCIII for use in decreasing ApoCIII to treat, prevent, or ameliorate diseases, disorders or conditions related to ApoCIII. Certain diseases, disorders or conditions related to ApoCIII include inflammatory, cardiovascular and / or metabolic diseases, disorders or conditions. The conjugated oligomeric compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.

The invention relates to a novel process for generating N-acetylgalactosamine (GalNAc) clusters using a nitrilase and conjugating said GalNAc clusters to oligonucleotides, such as oligonucleotides for use in therapy. In particular, the nitrilase is used to catalyse the conversion of a trinitrile intermediate to a triacid intermediate.

The invention relates to uridine diphosphate-N-difluoroacetyl galactosamine as well as a preparation method and application thereof. The chemical structure of the UDP-GalNDFA is similar to that of a natural substrate UDP-GalNAc, and the core difference is that N-acetyl at the site 2 of the UDP-GalNDFA is replaced by N-difluoroacetyl. The preparation method comprises the following steps: (1) preparing difluoroacetyl galactosamine; and (2) preparing the UDP-GalNDFA by taking the difluoroacetyl galactosamine as a substrate. As a novel artificial donor sugar, the UDP-GalNDFA has the characteristics of high activity, difficulty in hydrolysis and capability of being artificially synthesized. Compared with the existing donor sugar UDP-GalNTFA, the glucose UDP-GalNTFA has higher catalytic activity on glycosyl transferase, has stronger stability, is not easy to hydrolyze, and can be used as a donor substrate for synthesizing a chondroitin oligosaccharide skeleton, a chondroitin oligosaccharide intermediate and a chondroitin oligosaccharide derivative by a chemical enzyme method.