42 results about "De ubiquitination" patented technology

The application discloses a PROTAC compound with RORgamma t receptor targeted degradation and purposes thereof, which is a compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof. e is a ligand capable of combining with an E3 ubiquitin ligase; the L is a linking group covalently combining at least one R e and at least one R W ; the R w is a target protein RORgamma t binding ligand; the application is based on the target point of RORgamma t and the PROTAC technology, and a series of RORgamma t-PROTACs are designed and synthesized for the first time. The mechanism is that the target protein ligand and the E3 ubiquitin ligase ligand are combined with POI and E3 ligase respectively, so as to form a ternary complex of "POI-PROTAC-E3 ligase". Then, the POI is marked with a ubiquitination label, and is degraded by a proteasome. The advantages of RORgamma t-PROTACs mainly include targeting of "undruggable proteins", small dosage, low toxicity, and difficulty in drug resistance. W -L-R e (I)

This invention discloses an enhanced CAR-T cell (CARTAC) capable of secreting a targeted membrane protein degrader and its applications. While retaining specific killing function, this cell can expand locally in tumors and continuously secrete the bispecific adaptor molecule scTAC. scTAC can recruit E3 ubiquitin ligases, mediate ubiquitination of tumor cell surface membrane proteins (such as PD-L1), and achieve targeted degradation via the lysosomal pathway, effectively reversing the immunosuppressive microenvironment, overcoming antigen heterogeneity, and eliminating antigen-negative tumor cells through the bystander effect. This invention also utilizes the efficient endocytosis properties of EGFR to design scTAC-dual, which can further enhance degradation efficiency. In various lung cancer mouse models, CARTAC-dual exhibited excellent tumor infiltration capacity, low exhaustion levels, and sustained antitumor activity, without systemic toxicity. This invention integrates the targeted killing and protein degradation delivery functions of CAR-T cells, not only enhancing the control effect on solid tumors but also possessing target scalability, making it suitable for the universal upgrading of various CAR-T products.

The application discloses a method for preparing rice with changed tiller number, and belongs to the technical field of genetic breeding. The method comprises the following steps: introducing a coding gene of an OsD14 mutant into target rice to obtain rice with changed tiller number, wherein the tiller number of the rice with changed tiller number is higher or lower than that of the target rice, and the OsD14 mutant is a protein obtained by mutating the 10th, 11th, 13th and 15th amino acids in SEQ ID NO: 1 into other amino acids and keeping other amino acids in SEQ ID NO: 1 unchanged. It is proved by experiments that whether ubiquitination degradation of the OsD14 occurs is related to a phosphorylation state of the OsD14, the number of rice tillers is adjusted by using the phosphorylation state of the OsD14, and the plant type is improved, so that the yield of the rice is improved, and the method has a wide application prospect.

The application discloses a use of ubiquitination as a marker of systemic juvenile idiopathic arthritis, and relates to the technical field of biomedicine. The marker provided by the application is a gene combination of at least two genes in ubiquitination which participates in the occurrence of sJIA inflammation by mediating NLRs pathway; the ubiquitination includes HP, S100A9, S100A12, S100A8, IL6, CFH and UBE2D1; and the gene combination at least includes a combination of any one of HP and IL6 and UBE2D1. The application constructs a joint detection scheme of UBE2D1 and inflammatory factors, chemotactic factors or immune-related molecules, and can make up for the problems of insufficient stability or limited specificity of a single index to some extent, thereby improving the auxiliary diagnosis efficiency on sJIA. Meanwhile, the detection object involved in the application is clear, the detection mode is feasible, the detection can be carried out based on a blood sample, and the application has the advantages of relatively simple operation, strong clinical implementability, convenience for development into a detection kit, a detection chip or a matching detection reagent.

The present application relates to the field of biotechnology, and more particularly to an inhibitory peptide targeting p53 protein and application thereof. The present application uses IDProMat to design and obtain the inhibitory peptide targeting p53 protein according to the core binding site of the binding interface of the p53 protein core domain and ASPP2, TSPYL5, iASPP and the like; the inhibitory peptide can bind to p53 protein, competitively block the interaction between E3 ubiquitin ligase COP1 and p53, inhibit the ubiquitination degradation of p53, restore the anticancer function of p53, and has good biological safety and metabolic stability, and is expected to be used for clinical treatment of ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer and the like.

The application discloses a preparation method and application of a Tau-derived minimum functional peptide targeting a CUL3-RhoA axis, and an amino acid sequence of the Tau-derived minimum functional peptide is shown as SEQ ID NO. 4: GNIHHKPGGGQVEVKSEKLD. The application of the Tau-derived minimum functional peptide targeting the CUL3-RhoA axis in the preparation of a drug for treating diseases related to over-activation of osteoclasts belongs to the technical field of biological medicines, and the drug plays a pharmacological effect by blocking RhoA ubiquitination through CUL3, activating a RhoA-ROCK-MLC2 tension axis, and destroying a closed loop of osteoclasts. The Tau-derived minimum functional peptide can avoid application defects of full-length proteins, has low toxicity, high selectivity and physiological friendliness.

To provide a method for treating a disease. [Solution] The present invention provides compounds, compositions thereof, and methods for using them for targeted degradation of proteins and for treating protein-mediated disorders. The present invention relates particularly to compounds and methods useful for regulating targeted ubiquitination of various polypeptides and other proteins that are degraded and / or otherwise inhibited by the compounds according to the present invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods for using said compositions in the treatment of various disorders.

The application discloses a kind of PROTAC molecules with crizotinib as target head, preparation method and application, belong to the field of biological medicine;Preparation method includes: chloro carboxylic acid, thionyl chloride and anhydrous DMF are mixed, after heating reflux reaction, remove thionyl chloride, obtain acyl chloride;Pomalidomide, acyl chloride, organic solvent are mixed and reacted, then filtered to obtain intermediate M;Intermediate M, crizotinib, Na2CO3 are mixed and reacted, then filtered to obtain the PROTAC molecule with crizotinib as target head.The in vitro biological evaluation shows that the new PROTAC molecule can efficiently and selectively induce ubiquitination and degradation of target protein, and exhibits significant antiproliferative activity in drug-resistant tumor cell models and animal models;The application proves that the PROTAC molecule has great potential in overcoming drug resistance of traditional inhibitors, and provides a promising lead compound for developing new therapies for treating refractory diseases such as cancer.

This invention relates to a compound based on CRBN ligand-induced ubiquitination degradation of Hsp90, its preparation method and uses, as shown in X-Y-Z, where X represents the ligand of HSP90 protein, Z represents the ligand of E3 ligase, and Y represents the chain connecting X and Z. This type of compound can be used to treat or prevent tumors.

This invention belongs to the field of biopharmaceutical technology and provides the application of 16-dehydroprogesterone as a CRABP2 inhibitor in the treatment of non-small cell lung cancer (NSCLC). This application involves using 16-dehydroprogesterone to prepare a drug for treating NSCLC. This invention evaluates the therapeutic effect of 16-dehydroprogesterone on NSCLC using in vitro cell experiments, animal models, and organoid models. The results show that 16-dehydroprogesterone can disrupt the interaction between CRABP2 and PGC-1α, promote FBXW7 ubiquitination and degradation of PGC-1α, and reduce OXPHOS pathway activity, thereby inhibiting mitochondrial metabolism and inhibiting the growth of NSCLC cancer cells, thus achieving the treatment of NSCLC.

This invention discloses a specific antibody for identifying K27 ubiquitin chains, belonging to the field of biomedical technology. The antibody is obtained through structural simulation, molecular docking, and site-directed mutagenesis, using the initial screening antibody zl1901 as a parent material. The optimal core strain is zl1901-R3-S8, whose light chain CDR1 and CDR2 regions can bind tightly to the receptor and donor ubiquitin of K27-diUb, while the heavy chain CDR3 region forms a specific hydrogen bond with the P19 residue of the K27-diUb donor ubiquitin. The antibody of this invention exhibits an affinity (KD) of 16.5 nM for K27-linked ubiquitin chains, shows no cross-binding with M1, K6, K11, K48, and K63-linked ubiquitin chains, and only exhibits a very weak binding with K29-diUb. This allows for precise identification of endogenous and exogenous K27-linked ubiquitination modifications, providing a core tool for studying the regulatory mechanism of K27 ubiquitination.

This invention belongs to the field of plant genetic engineering and relates to the application and method of reducing the expression of the Zm7649 gene in improving plant stress resistance. This invention utilizes an EMS mutant with premature termination of expression. Zm7649-ems Heterologous overexpression with Arabidopsis thaliana Zm7649-OE Verified Zm7649 The function of negatively regulating salt stress and high temperature stress was studied, and its preliminary analysis was performed. Zm00001d027649 The molecular mechanism regulating stress involves the interaction between Zm7649 and a maize catalase (Zm4848), with ubiquitination degrading Zm4848 and reducing its protein stability. This invention provides new genetic resources and theoretical basis for maize stress-resistance breeding or germplasm innovation.

This invention discloses the use of LAPTM5 in the preparation of drugs regulating renal tubular epithelial-mesenchymal transition (EMT). Through bioinformatics analysis and multi-level experimental verification, this invention found that LAPTM5 is significantly upregulated in an aging kidney model and is positively correlated with renal aging and the severity of fibrosis. Mechanistic studies show that LAPTM5 interacts with the deubiquitinating enzyme USP10 and promotes its lysosomal degradation, weakening the deubiquitination effect of USP10 on PTEN. This leads to proteasomal degradation of PTEN via the K48-linked polyubiquitination pathway, thereby relieving PTEN's inhibition of the PI3K / AKT / mTOR signaling pathway, inhibiting autophagy activity, promoting renal tubular epithelial-mesenchymal transition, and accelerating the process of renal fibrosis. At the cellular level, PTEN overexpression can rescue LAPTM5-induced EMT; in animal models, the PTEN agonist matrine significantly improves D-galactose-induced renal fibrosis in aging mice and protects renal function by restoring autophagy.

The application discloses a nucleic acid molecule targeting SARS-CoV-2 virus Spike protein, a recombinant expression vector comprising the same and application. The nucleic acid molecule comprises a promoter and a downstream regulatory sequence, wherein the regulatory sequence comprises an antisense oligonucleotide, a nucleic acid sequence encoding a RING domain of TRIM21 and a nucleic acid sequence encoding a specific binding domain of a target protein. The design simultaneously realizes translation inhibition and ubiquitination degradation of the target protein through a single vector, significantly improves the inhibition efficiency of the target protein and provides a new efficient and simple strategy for protein targeted degradation.

The application discloses an HSC70 protein K128R mutant and application thereof in regulating CMA activity. The application discloses application of ubiquitination modification of an HSC70 protein at a K128 site in regulating chaperone-mediated autophagy. It is found for the first time that the HSC70 protein is subjected to K11-connected polyubiquitination under metabolic stress, and the modification site is a lysine at the 128th position (K128). The modification is mediated by a ROS-ATM-Atg7-TRIM21 signal axis, and is a necessary condition for the combination of the HSC70 and a lysosome membrane receptor LAMP2A to be enhanced and CMA to be activated. By constructing a K128R mutant, it is proved that the modification loss can block the response of CMA to metabolic stress. The application provides a new diagnostic marker and a drug target for CMA-related diseases (such as tumors and neurodegenerative diseases), and has important clinical application value.

This article provides compounds (e.g., compounds of formula (la)) that recruit LRRK2 protein or its mutant form to E3 ubiquitin ligases for targeting ubiquitination and subsequent proteasome degradation.

The invention provides compounds that degrade the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein including mutant forms via the ubiquitination of the KRAS protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers.

The application discloses a compound for degrading a target protein in a ubiquitin-proteasome system and a preparation method and application thereof, and a structural general formula of the compound is shown as formula I: R a -linker-SP-linker-R b Formula I; wherein, R a is an E3 ubiquitin ligase ligand; R b is a target protein ligand; SP is a sulfonyl pyridine, a chemical structural formula is shown as formula II; and linker is selected from succinic anhydride, glutaric anhydride, -CO-R 1 -CO- or -NH-R 2 -CO-, wherein, R 1 and R 2 are each independently selected from any substituted C1-C6 alkylene. The compound SD02 for degrading a target protein in the ubiquitin-proteasome system of the application significantly induces polyubiquitination of a STING protein, the SD02 effectively degrades the STING protein through the ubiquitin-proteasome system, in addition, the SD02 shows a dose-dependent reduction of phosphorylation levels of TBK1 and IRF3, can reduce mRNA levels of interferon-related genes induced by SATE-3', 3'-c-di-dAMP, and the SD02 has a cell growth inhibition effect on THP1, U937 and U2OS cells, and the SD02 does not hinder cell proliferation even at a high concentration.

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 present invention relates to novel compounds and method for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and cancer. Compounds of the invention include compounds having the formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R8, R9, R10, R12, Z, Y and m are as defined herein.

This invention discloses a short peptide and its derivatives that mimic the N-terminus of RhoE, and their pharmaceutical applications in the treatment of myocardial hypertrophy, belonging to the field of biomedical technology. This short peptide precisely mimics the amino acid sequence from position 1 to 20 of RhoE, specifically binding to the WW domain of WWP2 and competitively blocking the interaction between the N-Loop and C-Loop of its HECT domain. This causes the WWP2 conformation to change from a self-inhibited "closed" state to an activated "open" state, activating E3 ligase activity. The short peptide retains its binding ability to the cardiomyocyte membrane cavernin CAV3, allowing it to efficiently enter the cardiomyocyte cytoplasm via the cavernin endocytosis pathway, overcoming the deficiency of traditional drugs in clearing intracellular pathogenic proteins. Peptide derivatives constructed by fusing transmembrane peptides such as TAT ​​and T7 further improve intracellular delivery efficiency. Experiments have demonstrated that this short peptide and its derivatives can significantly promote WWP2 self-ubiquitination, enhance cardiomyocyte autophagic flux, clear intracellular pathogenic proteins, and effectively inhibit cardiomyocyte hypertrophy, making it suitable for the preparation of anti-myocardial hypertrophy drugs.

The present invention relates to a 3,4-dihydrophthalazine-1(2H)-one compound represented by formula (I), pharmaceutically acceptable salts thereof, prodrugs, stable isotope derivatives, isomers, solvates, or polymorphs thereof, and pharmaceutical compositions comprising the above compound. Furthermore, the present invention also provides a method for preparing the compound represented by formula (I). The compound is used as a modulator of targeted ubiquitination, particularly for the treatment of diseases related to the CRBN protein. The compound is also used for the preparation of related proteolytic chimeric molecules (PROTACs) for CRL4 CRBN It can also be used as a ligand for E3 ubiquitin ligase. JPEG2026520709000104.jpg38149

This invention discloses a long non-coding RNA that regulates protease degradation, its inhibitor, and its applications, belonging to the field of cell biology. The nucleotide sequence of the long non-coding RNA is shown in SEQ ID NO.1, and the reagent for inhibiting the long non-coding RNA includes knocking out the shRNA expressed by the long non-coding RNA. This invention enhances the ubiquitination modification of HK1 by knocking down lncHBHK1 (NONCODE database name: RP11-675F6.3), thereby accelerating the degradation of HK1 protein and inhibiting the proliferation of liver cancer cells. Combined with animal experiments, it is further confirmed that knocking down the expression level of this lncRNA in vivo can inhibit the growth of liver cancer tumors, indicating that this lncRNA has the potential to serve as a novel therapeutic target for liver cancer and provides a new strategy for developing drugs to treat liver cancer.

This invention provides the application of succinate compounds with PRL2 enzyme activity inhibition and targeted degradation functions in the preparation of antitumor drugs, belonging to the field of biomedical technology. The compounds of Formula I, or their stereoisomers, structural analogs, derivatives, or pharmaceutically acceptable salts, isolated from the traditional Chinese medicine Bletilla striata, possess dual functions of PRL2 enzyme activity inhibition and protein degradation. They mediate PRL2 ubiquitination and degradation by recruiting the E3 ubiquitin ligase TRIM25 and enhancing the interaction between PRL2 and TRIM25. The succinate compounds provided by this invention exhibit significant antitumor activity in in vitro and in vivo ovarian cancer models, providing new drug candidates for ovarian cancer treatment. Formula I

Deubiquitinase-targeting chimeras (DUBTACs) are an emerging class of therapeutics that can stabilize tumor suppressors by hijacking a deubiquitinase (DUB), thereby offering a strategic pivot from conventional approaches to target tumor suppressors. However, only OTUB1 and USP7 have been harnessed for DUBTAC development to date. Here, we show for the first time that USP28 can be leveraged for developing DUBTACs. Utilizing a USP28 non-covalent ligand, we crafted USP28-recruiting DUBTACs that effectively stabilized the ΔF508-CFTR mutant protein, with comparable effectiveness to the previously reported OTUB1- and USP7-recruiting CFTR DUBTACs. Furthermore, we developed USP28-recruiting cGAS DUBTACs that effectively stabilized cGAS, elevated the cGAS-STING signaling pathway, and elicited an anti-proliferative effect. We also developed first-in-class PPARγ DUBTACs to intervene with cancer metabolism pathways. Our lead PPARγ DUBTACs effectively stabilized PPARγ and suppressed the proliferation in cancer cells, thus providing a new potential anti-cancer therapeutic approach. Hence, this work advances the targeted protein stabilization field.

The present invention provides a method for producing reticulocytes containing increased levels of target protein or polypeptide. [Solution] The method comprises (a) preparing a erythrocyte precursor capable of expressing the target protein or polypeptide, (b) expressing the target protein or polypeptide, and (c) maturing the erythrocyte precursor into a reticulocyte, wherein the target protein or polypeptide is configured and / or inhibited so as to interfere with or prevent ubiquitination of the target protein or polypeptide when the erythrocyte precursor is matured into a reticulocyte. Erythrocytes, pharmaceutical compositions and related methods of use, as well as a method for screening proteins or polypeptides that are degraded by ubiquitination during the maturation of erythrocyte precursors, are also provided.

The application belongs to the technical field of biological pharmacy, discloses application of RING1 in inhibition of esophageal squamous cell carcinoma metastasis through ubiquitination degradation of Integrin alpha 5, and provides application of a RING1 activator in preparation of a drug for treating metastatic esophageal squamous cell carcinoma. The application systematically evaluates the inhibiting effect of RING1 on esophageal squamous cell carcinoma metastasis through in-vitro cell experiments and a mouse in-vivo metastasis model; the results show that RING1 inhibits the activation of the FAK signal pathway by mediating K11 type ubiquitination degradation of Integrin alpha 5, and then inhibits the adhesion, migration ability and in-vivo metastasis ability of ESCC cells.

The application discloses application of DNMT3B as a marker in preparation of a severe EV71 infection diagnosis product, and belongs to the biomedical field. It is found by the application that the nucleocytolysis degree and ubiquitination level of DNA methyltransferase DNMT3B can be used for diagnosing children with severe EV71 infection. EV71 infection promotes partial transport of DNMT3B in the cell nucleus to the cytoplasm, and promotes K63 ubiquitination modification of DNMT3B by combining the 3C and 3D proteins with DNMT3B, so that DNMT3B is finally degraded by a proteasome. The reagent for detecting the nucleocytolysis degree of DNMT3B and / or the reagent for detecting the ubiquitination level of DNMT3B can be used for preparing a severe EV71 infection diagnosis product or a severe EV71 infection prognosis diagnosis product, so as to realize diagnosis of severe EV71 infection or prognosis thereof.