57 results about "Proteasome" patented technology

The invention discloses 5 alpha-reductase degradation molecules as well as a preparation method and application thereof, four 5 alpha-reductase degradation molecules can realize thorough removal of zymoprotein by inducing proteasome-dependent degradation of 5 alpha-reductase instead of only inhibiting the activity of the 5 alpha-reductase, so that a more lasting treatment effect is obtained; under the condition of equal dosage, the effect of the 5 alpha-reductase degradation molecule on treating the benign prostatic hyperplasia is superior to that of the traditional inhibitor finasteride; the four kinds of 5 alpha-reductase degrading molecules can effectively degrade 5 alpha-reductase protein and remarkably inhibit development of benign prostatic hyperplasia, have good biological safety and provide new strategies and candidate drugs for treatment of diseases related to 5 alpha-reductase such as benign prostatic hyperplasia, prostatic cancer, androgenetic alopecia and acne.

Disclosed herein are multifunctional polypeptides comprising an optional signal peptide sequence, a cell penetrating peptide, an antigen binding domain (e.g., anti-synuclein, anti-tau, anti-huntingtin), and a programmable proteasome-targeting PEST motif, and methods for using these polypeptides in treatment of protein aggregation diseases, e.g., neurodegenerative diseases.

Disclosed is a method of treating a neurodegenerative disease such as Parkinson's disease, diffuse Lewy body disease, transitional Lewy body dementia, and multiple system atrophy in a subject. The method comprises administering to the subject a therapeutically effective amount of a peptide comprising an α-synuclein binding domain operably linked to a protein transduction domain and a proteasomal targeting domain, wherein the α-synuclein binding domain is derived from a reversed sequence of β-synuclein. Other methods, as well as uses and compositions, are disclosed.

The invention discloses an engineered protein and application thereof in mediating non-ubiquitination degradation, and belongs to the technical field of biological medicine. The structural domains CATCH1 and CATCH2 of the MIDN protein and the region between the structural domains CATCH1 and CATCH2 are modified for the first time, the modification mode comprises the steps that the structural domains CATCH1 and CATCH2 and the region between the structural domains CATCH1 and CATCH2 are replaced with antibodies or polypeptides, then structure or sequence optimization is conducted on the basis, and the obtained MIDN engineered protein not only retains the proteasome binding capacity of MIDN, but also has the advantages of being capable of improving the protein quality and the like. According to the present invention, the MIDN-based target protein degradation system has the MIDN-based target protein degradation system, can expand the target range to the membrane protein or the cytoplasm protein, can improve the degradation efficiency of the MIDN-based target protein degradation system, further has the antibody-mediated target protein specificity so as to achieve the pathological / physiological protein distinguishing effect, and does not have the obvious toxicity; therefore, the engineered protein provided by the invention has a good application prospect.

This invention discloses a PROTAC chimera for targeted degradation of ALKBH5, its preparation method, and its applications. The structural formula of the PROTAC chimera is shown in Formula I. The PROTAC chimera provided by this invention achieves specific ubiquitination modification and proteasome-dependent degradation of the ALKBH5 protein, completely eliminating the target protein function from its source. This invention overcomes the inherent limitations of traditional small molecule inhibitors, which can only reversibly block ALKBH5 enzyme activity, cannot eliminate the target protein, easily induce compensatory upregulation of the target protein, and develop drug resistance. It provides a novel and precise targeted therapy strategy for ALKBH5-driven malignant tumors.

Provided herein is an epoxyketone peptide immunoproteasome inhibitor having a structure: Formula (I) wherein X is a counterion, crystal forms, salts and processes for its preparation, and compositions thereof.

Compounds (I), compositions, and methods for use in degrading Aurora kinase are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising Aurora kinase degraders, as well as methods for treating cancer using Aurora kinase degraders.

Levels of expression of antibiotic resistance genes are increased up to six-fold by inserting a proteasome-targeting tag into transgenes expressed in eukaryotic cells. Various selectable marker proteins are combined with different destabilization domains, leading to up to 70% increase in transgene expression. The increase in expression varies highly depending on the engineered construct and the lines cells used. Increase in expression drives exosome loading of cargo proteins in some aspects. By increasing expression and by editing trafficking signals of cargo proteins, proteins that normally locate to the ER can be trafficked to exosomes. This disclosure discloses efficient exosome delivery of a wide variety of engineered proteins, including modified antigen proteins of SARS-CoV-2 and influenza, and other proteins such as a modified alpha galactosidase A, an extracellular domain of vascular endothelial growth factor fused to a constant region of a human immunoglobulin heavy chain, and modified trastuzumab heavy and light chains.

The invention relates to the technical field of medicines, in particular to application of huperzine A in treatment of beta-thalassemia. It is found for the first time that the anti-Alzheimer disease drug huperzine A can be directly combined with gamma-globin to inhibit degradation of gamma-globin through a ubiquitin-proteasome pathway, so that the stability of gamma-globin and the fetal hemoglobin level are improved; the abnormal erythropoiesis and hemolysis phenotype of the beta-thalassemia are improved under the condition of not changing the mRNA expression. Animal experiments show that huperzine A obviously improves hematocrit and the number of red blood cells, reduces the size distribution width of the red blood cells and the proportion of reticulocytes, relieves oxidative stress, hemolysis, splenomegaly and iron overload, and has no obvious liver and kidney toxicity. The invention creatively provides a new strategy for improving HbF by regulating and controlling protein homeostasis instead of transcriptional up-regulation, and provides a new drug action mechanism and application direction for treatment of beta-thalassemia and other hemoglobin diseases.

The invention discloses application of deaminotyrosine in improvement or prevention and treatment of muscular atrophy, and relates to the technical field of biological medicines. The invention finds that in the cellular level, DAT can effectively resist C2C12 myoblast senescence induced by etoposide; in a dexamethasone-induced C2C12 myotube atrophy model, DAT not only inhibits myotube diameter reduction from the form, but also down-regulates mRNA expression of key atrophy genes Atrogin-1 and MuRF-1 from the molecular level, and inhibits excessive activation of a ubiquitin-proteasome system; in-vivo animal experiments prove that DAT can reverse aging-related dyskinesia of rapidly-aged SAMP8 mice, and gait parameters of the rapidly-aged SAMP8 mice are all remarkably improved. According to the invention, a complete evidence chain from cells to the whole is constructed, and the DAT is proved to improve the senescent skeletal muscle atrophy through multiple ways of intervening cell senescence, antagonizing protein degradation, improving muscle microenvironment and the like, and shows important potential application value.

The invention provides SETDB1-targeting PROTAC as well as a preparation method and application thereof, and relates to the technical field of clinical medicine. The PROTAC comprises a nucleic acid aptamer capable of being specifically combined with SETDB1 protein, a connexon and a ligand for recruiting E3 ubiquitin ligase, wherein the ligand for recruiting the E3 ubiquitin ligase is thalidomide. The PROTAC can recruit the E3 ligase CRBN in cancer cells onto the SETDB1, and degrade the SETDB1 in a proteasome dependent manner. Therefore, the PROTAC can inhibit proliferation and migration of cancer cells; the killing effect of CD8 + T cells on cancer cells is enhanced, and the growth of the cancer cells is inhibited. Tests prove that the potential application of the PROTAC based on the aptamer in SETDB1 degradation in tumor cells provides a promising strategy for cancer treatment.

The present invention provides a use of a novel chromone derivative as a preventive and therapeutic agent for fibrosis. The compound can effectively prevent, ameliorate, or treat fibrosis by inhibiting TGF-beta signaling and inducing autophagy, by means of proteasome inhibition.

The invention discloses application of carfilzomib in preparation of a medicine for preventing and treating Nipah virus, and belongs to the technical field of medicine. The method mainly aims at ubiquitination modification of nipah virus M protein, the carfilzomib is used for inhibiting a host proteasome path, free ubiquitination factors in cells are depleted to achieve the effect of inhibiting ubiquitination of the M protein, then nucleoplasm shuttle of the M protein is inhibited, replication of the nipah virus is inhibited, and the effect is good. At present, most of research and development of virus medicines and vaccines are designed or modified aiming at viruses, a new thought is provided for research and development of medicines and vaccines in the future, and a new application is also provided for Carfilzomib.

This invention provides the application of chlorogenic acid in the preparation of drugs for treating intranuclear inclusion body disease (NIID), belonging to the field of pharmaceutical technology. This invention utilizes widely available sources with abundant safety data. Compared to novel chemical entities, chlorogenic acid, with its lower development risk, is used as a raw material. It has been found that chlorogenic acid can enhance the interaction between polyG protein and the E3 ubiquitin ligase TRIM21, forming a stable TRIM21-chlorogenic acid-polyG ternary complex. This promotes polyG ubiquitination and proteasome-dependent degradation, thereby reducing intracellular inclusion body burden and alleviating NIID from its pathological root cause. This provides a safe, effective, and highly specific new targeted therapeutic strategy for NIID.

The invention provides an MITF protein degradation agent and application thereof, and particularly provides a compound or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug thereof, and the compound is shown as a formula (I). The compound can degrade MITF protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the MITF protein.

The present disclosure provides modulators of proteasome dynamics and / or function in a mammalian cell, compositions and uses thereof. The disclosed modulating compounds are characterized by affecting at least one of: mammalian target of rapamycin (mTOR) activation and / or lysosomal association, proteasome cellular localization, the activity and / or level / s and / or the post translational modification / s (PTM / s), and / or subcellular localization of at least one signaling molecule participating directly or indirectly in at least one pathway mediating said proteasome dynamics / function.

The invention provides a composition for improving metabolism, a preparation method and a tea drink. Relates to the technical field of food. The composition for improving metabolism provided by the invention is prepared from the following raw materials: a mixed composition, a combined strain and a lactic acid bacteria fermentation product, experiments prove that the composition formed according to the formula can significantly improve the activity of proteasomes, the content and the activity are positively correlated, and the mixed composition, the combined strain and the composition of the lactic acid bacteria fermentation product all have obvious promotion effects and obvious synergistic interaction phenomena; the scheme of the invention can significantly reduce the generation rate of AGEs, and the content is in negative correlation with the metabolism efficiency of the human body, so that the scheme of the invention has the ability to improve metabolism.

The invention relates to a PIKfyve protein degradation agent and application thereof, and particularly provides a compound with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can degrade PIKfyve protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the PIKfyve protein.

The present invention discovers a compound capable of promoting proteasome activation contained in a Juniperus persica extract, and provides cosmetics, foods, pharmaceuticals and the like and / or raw materials incorporated therein for activating proteasomes in cells such as human skin cells using the compound to create a beautiful appearance. A proteasome activator containing, as an active ingredient, one or more compounds represented by formula (I) or formula (II) or a modified body thereof. (In the formula, R1 and R2 each independently represent a hydrogen atom, a hydroxyl group, a methoxy group, an acetoxy group, or a glucosyl group, and R3 each independently represent a hydrogen atom, a hydroxyl group, or a methoxy group)

The application discloses a proteolysis body (PROTAC) targeting HIV protease and application thereof, the PROTAC is a polypeptide structure, a general formula is R1-L-E3L or R1-L-E3L-R2, wherein R1 is a target ligand of HIV protease, L is a GSGS linker, E3L is a ligand of VHL (von Hippel-Lindau) E3 ubiquitin ligase, and R2 is a D-configuration arginine cell penetration peptide; the PROTAC can recruit E3 ligase, specifically induce ubiquitination and degradation of HIV protease in a proteasome-dependent manner; the application further provides a gene encoding the PROTAC, a recombinant carrier, a pharmaceutical preparation and application of the gene in preparation of an anti-AIDS drug.

The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

The application discloses a kind of multilocular hydatid Em Preparation method of 6B protein and application thereof in preparation of anti-host inflammatory response preparation. By protein structure modeling, molecular docking technology, it is confirmed that Em 6B can be combined with host 26S proteasome key subunit with high affinity, affect the assembly of host proteasome in vivo, and then intervene the activity of NF-κB signal pathway, so as to regulate host inflammatory response. Through animal experiment, it is shown that recombinant Em 6B intervention can significantly alleviate the colon injury of inflammatory bowel disease mice, regulate the expression level of pro-inflammatory and anti-inflammatory factors, and improve the survival rate of sepsis mice, and no obvious toxic side effects are observed. The application opens up a new path for developing anti-inflammatory preparations using parasite-host immune interaction natural molecules, and provides a kind of anti-host inflammatory response biological preparation technical scheme with novel mechanism of action and good biological safety, which has good application potential in the prevention and treatment of human and livestock inflammatory diseases.

Provided herein are compounds of formula (I) wherein Ra, Rb, Rc, A and p have the meanings given in the specification, as defined in formula (I), as well as pharmaceutically acceptable salts and solvates thereof, which are useful in the treatment of diseases in which pan-immune proteasome inhibition is desired or desired, and in particular in the treatment of cancer.

This invention discloses a multilocular echinococcosis larva. In Preparation method of -6B protein and its application in the preparation of anti-host inflammatory agents. Through protein structure modeling and molecular docking technology, the preparation method was confirmed. In -6B can bind with high affinity to a key subunit of the host 26S proteasome, affecting the assembly of the proteasome in the host and thus interfering with the activity of the NF-κB signaling pathway, thereby regulating the host inflammatory response. Animal experiments have shown that recombinant... In -6B intervention significantly alleviated colonic damage in mice with inflammatory bowel disease, regulated the expression levels of pro-inflammatory and anti-inflammatory factors, and improved the survival rate of septic mice, with no obvious toxic side effects observed. This invention opens up a new pathway for developing anti-inflammatory agents using natural molecules that interact with the parasite's immune system, and provides a novel mechanism of action and biosafety for anti-host inflammatory biological agents, showing great potential for application in the prevention and treatment of inflammatory diseases in humans and livestock.

The invention belongs to the technical field of biology, and particularly relates to separation and application of proteasome-rich human placenta-derived vascular stem cell outer vesicles. The extracellular vesicles provided by the invention are derived from human placenta source blood vessel promoting stem cells, and the human placenta source blood vessel promoting stem cells show that markers PAI-1 are positive, MECOM is positive, CD201 is positive, CD44 is positive, CD73 is positive, HLA-ABC is positive, CD34 is negative, CD31 is negative and CD326 is negative. Compared with human umbilical cord mesenchymal stem cell outer vesicles, the human placenta-derived vascular stem cell outer vesicles provided by the invention are rich in proteasomes and angiogenic protein factors, wherein the proteasomes have high chymotrypsin-like activity. Moreover, in-vivo and in-vitro experimental data show that the human placenta-derived vascular stem cell outer vesicles provided by the invention are rich in proteasomes, and can degrade accumulation of HIF and inhibit cell apoptosis; the medicine has a treatment effect on myocardial infarction.

The application discloses a plant-derived plastic-degrading enzyme and a method for degrading PP plastic in vitro, and belongs to the technical field of enzyme engineering. The plant-derived plastic-degrading enzyme is a plant-derived HIS1 protease. The method for degrading PP plastic in vitro comprises the following steps: cloning a HIS1 gene from a plant by using an RT-PCR technology; connecting the gene to a prokaryotic expression plasmid by using a blunt-end cloning technology; introducing the gene into an expression platform of Bl21 (DE3) E. coli to express and purify the HIS1 protein; and degrading PP plastic in an enzyme reaction environment constructed in vitro. The HIS1 protein provided by the application can effectively degrade PP plastic, provides a new idea for degrading plastic by using plant enzymes, and has a good application prospect.

Provided herein are methods for using RNAi molecules targeting a proteasome beta 5 (PSMB5) gene for controlling Coleopteran insects, methods for producing RNAi molecules targeting PSMB5, and compositions comprising RNAi molecules targeting PSMB5.

A biological composition has a mixture of mechanically selected allogeneic biologic material derived from bone marrow. The mixture has non-whole cellular components including vesicular components and active and inactive components of biological activity, cell fragments, cellular excretions, cellular derivatives, and extracellular components. The mixture including non-whole cell fractions including one or more of exosomes, transcriptosomes, proteasomes, membrane rafts, lipid rafts. The mixture is compatible with biologic function.

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). Provided are pharmaceutical compositions which include a mixture of a PROTAC, a hydrophilic polymer, a surfactant, and optionally an acid and an adsorbent. Also described are methods for preparing and using such pharmaceutical compositions. In one aspect, disclosed herein is an amorphous solid dispersion comprising PROTAC.

The invention provides a medicine for preventing and / or treating sterile looseness. The medicine is a proteasome inhibitor, and the proteasome inhibitor comprises a broad-spectrum inhibitor (such as bortezomib, carfilzomib and ixazomib) and an immune proteasome selective inhibitor (such as ONX-0914, KZR-616 and analogues thereof). The drug can be in a dosage form suitable for modes of articular cavity injection, bone cement slow release, prosthesis surface coating or systemic drug delivery and the like. The invention not only can be used for preparing the medicine for treating or preventing the sterile looseness, but also can be expanded to the development of a medicine carrying delivery system and an anti-rejection prosthesis material, and provides a new thought and a feasible way for preventing and treating the sterile looseness.