33 results about "Proteasome" patented technology

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.

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 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 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 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.

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 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.

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.

This invention relates to the field of antiviral drugs, specifically a dynamic equilibrium regulatory model for SUMOylation and K48K63 ubiquitination of the SARS-CoV-2 N protein, a targeted regulatory agent, and an application method. This invention uses a SUMOylation pathway inhibitor to block SUMOylation modification of the N protein; and / or in combination with a deubiquitinating enzyme inhibitor to maintain endogenous K48 ubiquitination signaling. By inhibiting SUMOylation, its spatial shielding of K48 ubiquitination is removed, and the N protein is rapidly degraded using the cellular endogenous ubiquitin-proteasome system, thereby inhibiting viral replication. This invention provides a pharmaceutical composition containing the above-mentioned active ingredients, a kit for detecting the modification status of the N protein, and its application in the preparation of anti-SARS-CoV-2 drugs. The technical solution of this invention is simple and feasible, the raw materials are readily available, no complex genetic engineering vector construction is required, and it has significant antiviral effects and extremely high transformation value.

The invention belongs to the technical field of biology, and particularly relates to a composition for improving the developmental potential of oocytes, an in-vitro maturation culture solution and an optimized culture method. And a CCR5 / CXCR3 antagonist. The preparation for in-vitro embryo production contains an Ephrin ligand family and a CCR5 / CXCR3 antagonist, the microenvironment for maturation culture of oocytes is synergistically optimized, further, sesquiterpenol compounds and / or phenylpropane compounds can be added on the basis, and therefore the preparation can be used for preparing the embryos in vitro by means of the synergistic effect of the components. The composition can effectively inhibit the formation of abnormal protein aggregates in oocytes, enhance the ability of proteasomes to remove error protein aggregates, significantly reduce the level of reactive oxygen species (ROS) and increase the content of endogenous antioxidant substances such as glutathione (GSH), so as to reduce the protein toxicity stress, oxidative stress and other dimensions, and thus, the composition can be used for preparing an anti-inflammatory drug. The quality and the fertilization rate of oocytes after in-vitro maturation and the development potential of subsequent embryos are remarkably improved, and the application prospect is wide.

Disclosed are a fusion protein comprising a ubiquitin receptor and uses thereof. Specifically, disclosed are a targeted protein degradation technology that directly uses the proteasome, a final organelle that performs protein degradation, as degradation machinery for pathogenic proteins, as well as a fusion protein comprising a ubiquitin receptor, which is a ubiquitin recognition subunit of a proteasome regulatory particle, and uses thereof.

A bifunctional chimera heterocyclic compound represented by formula (I) and targeting epidermal growth factor receptor (EGFR), and a pharmaceutical composition thereof, a preparation method therefor, and a use thereof. The compound recruits a ubiquitin ligase to EGFR, thereby promoting ubiquitination of EGFR and proteasomal degradation of EGFR. Research results show that the compounds exhibit good EGFR degradation activity and can be used for treating EGFR-mediated diseases.

The application provides an immunogenicity-based antigen peptide screening method and evaluation method, and belongs to the technical field of immunology.The application provides an evaluation method for candidate antigen peptides screened by a conventional machine algorithm, wherein the candidate antigen peptides are evaluated by polypeptide MHC binding affinity difference, immunogenicity calculation, probability of the candidate antigen peptide-MHC complex being recognized by a TCR, and antigen transporter (TAP) transport efficiency, proteasome cleavage and expression abundance.The application also provides an antigen peptide screening method, which comprises machine algorithm prediction, the above evaluation, ELISpot verification, IFN gamma flow sorting and co-culture with an organoid model, and finally embedding sectioning and Ki-67 immunohistochemical staining to screen immunogenic antigen peptides.The above screening will help to more accurately screen strong immunogenic neoantigen peptides.

The present disclosure provides bifunctional compounds as selective SMARCA2 degraders via ubiquitin proteosome pathway, and their therapeutic use for treating cancers.

The present invention relates to a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or an isomer thereof, and a pharmaceutical composition for treating or preventing proteasome-mediated diseases, comprising the same as an active ingredient.

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 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 belongs to the technical field of chemical medicine synthesis, and particularly relates to a proteolysis targeting chimera, a preparation method, a pharmaceutical composition and purposes thereof. The structural formula of the proteolysis targeting chimera is shown in formula Ia or formula Ib; the preparation process is simple and easy to operate; the proteolysis targeting chimera or pharmaceutically acceptable salt thereof prepared has the effect of efficiently degrading CDK2 / 4 / 6 / 9 and has high selectivity; and experimental results show that the compound can induce the targeted degradation of CDK2 / 4 / 6 / 9 protein by using the ubiquitin-proteasome system, inhibit the downstream signal pathway, realize the selective degradation of CDK2 / 4 / 6 / 9 at the protein level, cell level and animal level, and has a good effect of resisting the proliferation of prostate cancer cells.

The invention relates to an mRNA (messenger ribonucleic acid) vaccine containing a proteasome targeting structural domain as well as a preparation method and application thereof. The invention provides a nucleic acid molecule comprising a coding sequence of at least one antigen peptide and a coding sequence of at least one proteasome targeting domain. The mRNA vaccine can increase the presentation rate of antigen peptide, enhance T cell immunity, and improve the killing effect on tumor cells and the immunocompetence on exogenous viruses.

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

This invention proposes a nanoaggregate based on a near-infrared II aggregation-induced emission (AIE) material, its preparation method, and its application, belonging to the field of medical technology. The nanoaggregate of this invention is self-assembled from an AIE material and an amphiphilic carrier material, a DSPE-PEG series polymer. This nanoaggregate exhibits AIE properties in the near-infrared II region and can downregulate the expression of heat shock protein 70 through a proteasome-dependent mechanism. In vitro and in vivo experiments show that this nanoaggregate can achieve complete tumor ablation under low-temperature photothermal therapy at 43-45℃ without the need for combined use with exogenous heat shock protein 70 inhibitors, while simultaneously achieving near-infrared II fluorescence imaging guidance. This invention has the advantages of being single-component, low-toxicity, and integrating imaging and therapy, and has broad application prospects in the field of low-temperature photothermal therapy for tumors.