26 results about "Prohormone Convertases" patented technology

The invention relates to an shRNA (short hairpin Ribonucleic Acid) interference sequence of a targeted silence PCSK9 gene and a construction method and lipid-lowering application of a recombinant adeno-associated virus vector of the shRNA interference sequence. Hyperlipidaemia is a metabolic disease characterized by abnormal rising of cholesterol and triglyceride levels in blood, and the design of lipid-lowering drugs is the focus of attention to improvement of hyperlipidaemia. Proprotein convertase subtilisin / kexin type 9 (PCSK9) can be combined with a low-density lipoprotein receptor (LDL-R) and degrade the LDL-R, so that accumulation of LDL-C in blood is further promoted, and hyperlipidemia is caused. Aiming at the key target PCSK9, a specific shRNA interference sequence is designed, and a recombinant adeno-associated virus vector (rAAV) carrying the sequence is constructed by an enzyme digestion-connection method. In-vitro experiments prove that the vector can remarkably reduce the expression level of PCSK9 protein, so that the cyclic utilization of a low-density lipoprotein receptor (LDL-R) is promoted, and the concentration of low-density lipoprotein cholesterol (LDL-C) in plasma is reduced. The rAAV vector provided by the invention has the characteristics of low production cost, high transfection efficiency, lasting action time and the like, and provides a new thought for gene therapy of hyperlipidemia.

The present disclosure relates to small molecule inhibitors of proprotein convertase subtilisin-like / kexin type 9 (PCSK9), pharmaceutical compositions comprising said compounds, and their use in the prevention and treatment of diseases and disorders associated with PCSK9.

The present invention relates to methods of treating or preventing cholesterol related disorders, such as hypercholesterolemia, hyperlipidemia or dyslipidemia, using antibodies against proprotein convertase subtilisin / kexin type 9 (PCSK9). Formulations and methods of producing said formulations are also described.

The present invention relates to a dual-targeting siRNA agent comprising two distinct siRNAs targeting two different genes or their pharmaceutically acceptable salts, wherein the two distinct siRNAs or their salts are linked by a pharmaceutically acceptable ligand. The siRNA is a dsRNA composed of a sense strand and an antisense strand, and the two different genes are selected from a group consisting of angiotensinogen (AGT), proprotein convertase subtilisin / kexin type 9 (PCSK9), and human angiopoietin-like protein 3 (ANGPTL3). The present invention provides the application of the dual-targeting siRNA agent in the preparation of drugs for preventing or treating diseases associated with hypertension and / or dyslipidemia. The dual-targeting siRNA agent described in the present invention can effectively inhibit the expression of two target genes simultaneously in vivo, offering the advantages of strong non-antagonistic activity and high safety. The present invention also provides the siRNAs targeting corresponding genes for the aforementioned dual-targeting siRNA agent and their use for preventing or treating diseases associated with hypertension and / or dyslipidemia.

Compositions and methods relating to ApoA-1 fusion polypeptides are disclosed. The fusion polypeptides include a first polypeptide segment corresponding to an ApoA-1 polypeptide or ApoA-1 mimetic, and may also include a dimerizing domain such as, e.g., an Fc region, which is typically linked carboxyl-terminal to the first polypeptide segment via a flexible linker. In some embodiments, the fusion polypeptide further includes a second polypeptide segment located carboxyl-terminal to the first polypeptide segment and which confers a second biological activity (e.g., an RNase, paraoxonase, platelet-activating factor acetylhydrolase, cholesterol ester transfer protein, lecithin-cholesterol acyltransferase, polypeptide that specifically binds to proprotein convertase subtilisin / kexin type 9, or polypeptide that specifically binds to amyloid beta). Also disclosed are dimeric proteins comprising first and second ApoA-1 fusion polypeptides as disclosed herein. The fusion polypeptides and dimeric proteins are useful in methods for therapy.

The invention relates to a dual-targeting siRNA agent, which comprises two different siRNAs targeting two different genes or pharmaceutically acceptable salts thereof, the two different siRNAs or salts thereof are connected through pharmaceutically acceptable ligands, the s-RNA is dsRNA composed of a sense strand and an antisense strand, and the s-RNA is dsRNA composed of a positive-sense strand and a negative-sense strand. The two different genes are selected from two of angiotensinogen (AGT), proprotein convertase subtilisin 9 (PCSK9) and human angiopoietin-like protein 3 (ANGPTL3). The invention provides application of the dual-targeting s iRNA agent in preparation of drugs for preventing or treating diseases related to hypertension or / and lipid disorder. The dual-targeting siRNA agent can effectively inhibit expression of two target genes in vivo at the same time, and has the advantages of being high in mutual non-antagonistic activity and high in safety. The invention also provides the s iRNA of the corresponding gene of the dual-targeting s iRNA agent and application of the s iRNA to prevention or treatment of diseases related to hypertension or / and lipid disorder.

This invention relates to compounds of Formula I and their isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs, and polymorphs. The compounds of Formula I can be used as inhibitors of proprotein convertase subtilisin 9 (PCSK9), effectively inhibiting PCSK9 activity and reducing the concentration of low-density lipoprotein cholesterol in plasma, and have good application prospects in the preparation of drugs for the treatment or prevention of cardiovascular diseases.

A low-molecular weight compound having an activity of inhibiting the functions of proprotein convertase subtilisin / kexin type 9 (PCSK9), a PCSK9 inhibitor containing a compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as an active component, and a medicament containing the PCSK9 inhibitor as an active component for use in prevention or treatment of one or more symptoms, diseases, or disorders, related to the functions of PCSK9.

The present invention relates to methods of treating or preventing cholesterol related disorders, such as hypercholesterolemia, hyperlipidemia or dyslipidemia, using antibodies against proprotein convertase subtilisin / kexin type 9 (PCSK9). Formulations and methods of producing said formulations are also described.

An siRNA which inhibits proprotein convertase subtilisin / kexin type 9 (PCSK9) gene expression, a pharmaceutical composition containing the siRNA, and a conjugate. Each nucleotide in the siRNA is independently a modified or unmodified nucleotide. The siRNA contains a sense strand and an antisense strand. The sense strand contains nucleotide sequence I; nucleotide sequence I having the same length as the nucleotide sequence shown in SEQ ID NO: 1, with no more than three nucleotides differences. The antisense strand contains nucleotide sequence II, nucleotide sequence II having the same length as the nucleotide sequence shown in SEQ ID NO: 2, with no more than three nucleotides differences. The siRNA, pharmaceutical composition thereof and the conjugate can effectively treat and / or prevent hypercholesterolemia.

The invention discloses an application of polypeptide in preparation of antidepressant drugs, and belongs to the field of biological medicine, the polypeptide is neuropeptide PEN or a functional fragment and a derivative thereof, and the PEN is one of a plurality of derivative peptides formed by cutting a protein precursor proSAAS existing in a central nervous system of a mammal through proprotein convertase. Research finds that PEN as an endogenous polypeptide can significantly shorten the immobility time of a mouse in a tail suspension experiment and a forced swimming experiment and improve the depression-like behavior of the mouse, shows an obvious anti-depression effect, and has no obvious influence on the movement function of the mouse. A further research result shows that the anti-depression mechanism of PEN is related to inhibition of NMDAR2B / CaMKII signals of a mouse hippocampus and increase of ERK1 / 2 protein activity of the hippocampus. The invention discovers potential application of PEN in preparation of antidepressant drugs for the first time, and provides a new target and theoretical basis for development of novel, safe and effective antidepressant drugs.

An siRNA which inhibits proprotein convertase subtilisin / kexin type 9 (PCSK9) gene expression, a pharmaceutical composition containing the siRNA, and a conjugate. Each nucleotide in the siRNA is independently a modified or unmodified nucleotide. The siRNA contains a sense strand and an antisense strand. The sense strand contains nucleotide sequence I; nucleotide sequence I having the same length as the nucleotide sequence shown in SEQ ID NO: 1, with no more than three nucleotides differences. The antisense strand contains nucleotide sequence II, nucleotide sequence II having the same length as the nucleotide sequence shown in SEQ ID NO: 2, with no more than three nucleotides differences. The siRNA, pharmaceutical composition thereof and the conjugate can effectively treat and / or prevent hypercholesterolemia.

Provided herein are gene repressor systems comprising fusion proteins, such as fusion proteins comprising a DNA binding domain such as a TALE, zinc finger or catalytically-dead CRISPR protein and guide nucleic acid (gRNA), which are useful in the repression of a proprotein convertase subtilisin / kexin Type 9 (PCSK9) gene. Also provided are methods of using such systems to repress transcription of PCSK9.

The application discloses a polynucleotide sequence for simultaneously reducing blood fat and blood pressure and application thereof. Cell and mouse experiments show that the application can significantly inhibit the expression levels of multiple blood fat and blood pressure molecular targets such as proprotein convertase subtilisin / kexin type 9 (PCSK9), angiotensinogen (AGT) and beta-hydroxy-beta-methylglutaryl-coenzyme a reductase (HMGCR), thereby reducing the blood fat and blood pressure levels of a related disease model mouse. The application is expected to be applied to treating related cardiovascular and cerebrovascular diseases complicated with high blood fat and high blood pressure symptoms.

Aspects of the technology relate to a composition comprising: (i) a first RNAi agent that targets Proprotein convertase subtilisin / kexin type 9 (PCSK9) and a second RNAi agent that targets angiotensinogen (AGT); (ii) a first RNAi agent that targets PCSK9 and a third RNAi agent that targets Apolipoprotein A (LPA); (iii) a second RNAi agent that targets AGT and a third RNAI agent that targets LPA, or (iv) a first RNAi agent that targets PCSK9, a second RNAi agent that targets AGT, and the third RNAi agent that targets LPA.

To provide an in vitro method for assessing the risk of developing sepsis, systemic inflammatory response syndrome (SIRS), septic shock, or multiple organ dysfunction syndrome (MODS) in a subject. Also provided are pharmaceutical compositions for the treatment of sepsis, SIRS, septic shock or MODS in a subject.SOLUTION: Determining or having determined the presence or absence of i) a PCSK9 variant nucleic acid sequence encoding a Pro-protein convertase subtilisin / kexin type 9 (Arg46Leu) PCSK9; and ii) a low-density-lipoprotein receptor (LDLR) variant nucleic acid sequence comprising a single nucleotide polymorphism rs6511720 in a biological sample obtained from the subject, wherein the subject is a PCSK9 reference and being a LDLR reference indicates that the subject has an increased risk of developing SIRS / MODS.SELECTED DRAWING: None

Compositions and methods relating to ApoA-1 fusion polypeptides are disclosed. The fusion polypeptides include a first polypeptide segment corresponding to an ApoA-1 polypeptide or ApoA-1 mimetic, and may also include a dimerizing domain such as, e.g., an Fc region, which is typically linked carboxyl-terminal to the first polypeptide segment via a flexible linker. In some embodiments, the fusion polypeptide further includes a second polypeptide segment located carboxyl-terminal to the first polypeptide segment and which confers a second biological activity (e.g., an RNase, paraoxonase, platelet-activating factor acetylhydrolase, cholesterol ester transfer protein, lecithin-cholesterol acyltransferase, polypeptide that specifically binds to proprotein convertase subtilisin / kexin type 9, or polypeptide that specifically binds to amyloid beta). Also disclosed are dimeric proteins comprising first and second ApoA-1 fusion polypeptides as disclosed herein. The fusion polypeptides and dimeric proteins are useful in methods for therapy.

The present disclosure provides methods of treating subjects having sepsis, SIRS, septic shock, and / or MODS, methods of identifying subjects having an increased risk of developing sepsis, SIRS, septic shock, and / or MODS, and methods of detecting Proprotein Convertase Subtilisin / Kexin Type 9 (PCSK9) and / or Low Density Lipoprotein Receptor (LDLR) variant nucleic acid molecules and variant polypeptides.

The invention provides a liquid preparation containing an anti-PCSK9 (human proprotein convertase subtilisin / kexin type 9) antibody with high concentration. The preparation further comprises a buffer solution, a stabilizer and a surfactant. The liquid preparation provided by the invention has low viscosity, and the antibody has high stability after the preparation is stored for several months.

The invention relates to the technical field of biological medicine, in particular to a biomarker combination, a kit of the biomarker combination and application of the biomarker combination in diagnosis of acute Stanford B-type aortic dissection (ATBAD). The biomarker combination comprises serum amyloid protein A1 (SAA1), serum amyloid protein A2 (SAA2), C-reactive protein (CRP), neutrophil elastinase (ELANE), matrix metalloenzyme 9 (MMP9), nest protein 1 (NID1), mannose binding lectin 2 (LMAN2) and proprotein convertase subtilisin / kexin type 9 (PCSK9), and the biomarker combination can realize high-sensitivity and high-accuracy detection of ATBAD. And the anti-interference capability is excellent.

Provided herein are gene repressor systems comprising fusion proteins, such as fusion proteins comprising a DNA binding domain such as a TALE, zinc finger or catalytically-dead CRISPR protein and guide nucleic acid (gRNA), which are useful in the repression of a proprotein convertase subtilisin / kexin Type 9 (PCSK9) gene. Also provided are methods of using such systems to repress transcription of PCSK9.

The present invention relates to methods of treating or preventing cholesterol related disorders, such as hypercholesterolemia, hyperlipidemia or dyslipidemia, using antibodies against proprotein convertase subtilisin / kexin type 9 (PCSK9). Formulations and methods of producing said formulations are also described.

The present invention provides methods for treating a PCSK9-mediated disease or a PCSK9-mediated condition. Specifically, the invention relates to methods comprising the administration of a proprotein convertase subtilisin / kexin type 9 (PCSK9) antibody or antigen binding protein, in the absence of a statin, to a subject in need thereof.

The present invention provides pharmaceutical formulations comprising a human antibody that specifically binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9). The formulations may contain, in addition to an anti-PCSK9 antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.