17 results about "Deubiquitination" patented technology

The invention discloses a recombinant deubiquitination enzyme USP7 mutant, a preparation method and application of the mutant in tumor treatment, and belongs to the technical field of biomedicine.The USP7 mutant changes substrate selectivity through site-specific mutagenesis, specifically deubiquitination tumor suppression protein p53 is achieved, meanwhile, oncogenic protein MDM2 is unstable, a p53 anti-tumor pathway is activated, and the tumor suppression protein p53 is activated. The mutant induces cell cycle arrest and apoptosis in wild type p53 tumor cells, the ICvalue is 180-280nM, animal experiments show that the tumor growth inhibition rate reaches 72%, the tumor tissue enrichment is improved by 12 times by combining a folic acid targeted lipid nanoparticle delivery system, the drug resistance of an MDM2 inhibitor is overcome, the mutant has a synergistic effect with chemotherapeutic drugs, and the mutant can be used for preparing drugs for treating tumors. And a novel accurate treatment strategy is provided for wild-type p53 tumors.

The application belongs to the technical field of gene editing, and discloses a CBE editing protein and application. The CBE editing protein disclosed by the application is fused with a deubiquitination protein. It is found that, compared with ABE and other single-base editors, the protein of the CBE single-base editor is unstable and is rapidly degraded in cells. By fusing the deubiquitination protein, the stability of the protein of the CBE single-base editor is improved, so that the editing efficiency of the CBE is improved.

The invention provides an application of USP7 (ubiquitin-specific protease 7) as a target spot in preparation of drugs for treating vascular abnormal leakage diseases, and relates to the technical field of biomedicine, USP7 (ubiquitin-specific protease 7) as a deubiquitination enzyme not only regulates tumor, nerve and immune related diseases, but also is closely related to vascular endothelial cell functions. In the vascular homeostasis, the USP7 can maintain the integrity of a vascular barrier and inhibit pathological leakage by stabilizing endothelial connexin such as VE-cadherin and beta-catenin; under the inflammation or hypoxia condition, through deubiquitination of HIF-1alpha or NF-kappa B pathway components (such as I kappa B alpha), vascular endothelial cell activation can be promoted, VEGF signal-driven abnormal angiogenesis or release of inflammatory factors can be aggravated, and diabetic retinopathy, tumor vascular hyperplasia and sepsis-related vascular leakage can be participated. According to the application, verification experiments prove that USP7 has a certain protection effect on vascular permeability, and a treatment strategy is provided for vascular abnormal leakage diseases clinically.

The invention discloses an inhibitor for inhibiting a deubiquitinating enzyme USP20 protein or a coding gene thereof and application thereof, and belongs to the field of genetic engineering, the function and mechanism of a super enhancer (SE) regulation gene USP20 in T-ALL are found, a more effective targeted therapy strategy is expected to be developed, and a better clinical effect is brought to T-ALL patients. Specifically, firstly, a gene USP20 regulated by a super enhancer is found in T-ALL, and the gene USP20 is specifically and highly expressed in the T-ALL and plays an important role. The USP20 stabilizes the HIF1A protein through deubiquitination, and promotes the proliferation and survival of T-ALL cells. The USP20 specific inhibitor GSK2643943A provides a new thought for the treatment of the T-ALL, and the USP20 is expected to become a potential target spot for the treatment of the T-ALL.

The invention discloses application of MYSM1 regulation and control of ITPR1 mediated cell autophagy in inhibition of cervical cancer, and belongs to the technical field of biomedicine.The MYSM1 gene and / or expression or activity of encoded protein of the MYSM1 gene are / is up-regulated, and an MYSM1-ITPR1-autophagy signal channel is activated, so that proliferation, migration, invasion or epithelial-mesenchymal transition of cervical cancer cells is inhibited, and cervical cancer is inhibited. And / or promoting apoptosis of cervical cancer cells; wherein the MYSM1 activates the expression of ITPR1 through the activity of a deubiquitination enzyme which is subjected to single ubiquitination modification on the 119th lysine of histone H2A of the MYSM1, and the ITPR1 serves as an endoplasmic reticulum calcium ion channel to mediate calcium ion release so as to trigger cell autophagy. Based on the mechanism, the invention provides a new application of MYSM1 / ITPR1 in preparation of anti-cervical cancer drugs, a drug composition targeting the pathway, a candidate drug screening method and a kit for diagnosis and prognosis. The invention aims to solve the problem that a technical scheme for effectively inhibiting the malignant progression of cervical cancer by targeting an MYSM1-ITPR1 pathway is lacked in the prior art.

This invention belongs to the field of biomedical technology and provides a small molecule inhibitor and its application. Specifically, this invention provides the application of an inhibitor that inhibits the expression and / or content of Integrin β1 protein in the preparation of drugs for treating breast cancer. The inhibitor used to inhibit the expression and / or content of Integrin β1 protein is a POH1 inhibitor. This invention is the first to elucidate the deubiquitination and stability regulation of the transmembrane receptor Integrin β1 by POH1, identifies the DUB of Integrin β1 as POH1, and utilizes a small molecule inhibitor of POH1 to block POH1 and target Integrin β1. This provides a new precise model and method for the development of cancer drugs targeting integrins, promotes the application and translation of basic research, and contributes to new breakthroughs in tumor treatment.

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 invention discloses a method for predicting activity of ubiquitin ligase and deubiquitination enzyme. The method comprises the following steps: 1) collecting a real interaction set from an experimental verification database; merging the data set with a prediction interaction data set to obtain an integrated prediction set; 2) respectively matching quantitative ubiquitination omics data provided by a user with the real interaction set and the integrated prediction set, and extracting a Log2 difference multiple Log2 FC value in the quantitative ubiquitination omics data from matched entries; 3) calculating the enzyme activity of the real interaction set; 4) performing dynamic threshold optimization and screening on the integrated prediction set to obtain a comprehensive score; (5) selecting a threshold value which maximizes the comprehensive score as an optimal prediction confidence threshold value, and then screening out interaction data of which the confidence score is higher than the optimal prediction confidence threshold value from the integrated prediction set, (6) calculating the enzyme activity of the prediction set, and (7) constructing an enzyme activity prediction report based on results obtained in the steps (3) and (6).

The invention discloses a method for synthesizing a ubiquitin protein probe by enzyme mediation, which comprises the following steps: carrying out recombinant expression on ubiquitin protein HA-Ub (1-73)-NSL-His6 containing an OaAEP1 ligase recognition sequence, catalyzing by using OaAEP1-C247A ligase, efficiently loading a chemical warhead carrying a single glycine or double glycine motif to a ubiquitin protein substrate at a fixed point, and carrying out enzyme mediation to synthesize the ubiquitin protein probe. And purifying to obtain the high-purity ubiquitin probe. Compared with a traditional method, the complex chemical coupling step is omitted, and the method has the advantages of being easy and convenient to operate, high in yield, high in specificity, mild in reaction condition and the like and is suitable for large-scale preparation. The obtained probe can be widely applied to the fields of ubiquitination modification mechanism research, deubiquitination enzyme (DUBs) function analysis, drug development and the like, and an efficient tool is provided for analysis of a ubiquitination regulation and control network and disease treatment target research.

The invention relates to the technical field of bioinformatics and proteomics, and discloses a ubiquitination regulation mass spectrometry analysis system and method for a double-quantization model. Comprising a proportion acquisition module used for carrying out difference comparison on abundance of a modified peptide fragment and an unmodified peptide fragment before and after affinity enrichment in a site analysis workflow, and calculating an occupation proportion of ubiquitination sites according to a comparison result; the occupancy rate quantification module is used for acquiring occupancy rate quantification information in combination with the isotope labeling condition; the turnover rate quantification module is used for monitoring the attenuation rate of a ubiquitination site by blocking the activity of a specific ubiquitin activating enzyme by using an E1 enzyme inhibitor, and calculating the deubiquitination rate and the half-life period according to a corresponding monitoring result to realize turnover rate quantification; and the analysis completion module is used for completing ubiquitination adjustment mass spectrometry analysis by combining occupancy rate quantification and turnover rate quantification with a preset double-quantification model.

The application provides an application of auro-thio-pan in preparation of a drug for treating a USP6 gene rearrangement and abnormal activation disease, and the auro-thio-pan is a lipophilic gold-based compound. Researches of the application show that in addition to the USP6 gene rearrangement disease, tumors such as osteosarcoma, RUNX1 gene rearrangement and CBFbeta gene rearrangement leukemia, synovial sarcoma and the like also have abnormal activation of USP6, and are clinical application scenarios of USP6 inhibitors. It is further found that the compound auro-thio-pan can effectively combine with a catalytic domain of USP6 and inhibit the deubiquitination enzyme activity of USP6, and inhibit the growth of RUNX1 rearrangement tumors at the cell and animal levels. The application opens up a new direction for the development of a drug for treating the USP6 gene rearrangement and abnormal activation tumor and the like, and expands the application range of auro-thio-pan in the treatment of clinical diseases, and provides a possibility for improving the prognosis and survival of corresponding clinical disease patients.

The invention discloses application of a BHLHE22 gene in triple negative breast cancer, and belongs to the technical field of biological medicines. Data analysis shows that in triple negative breast cancer (TNBC), the expression of the BHLHE22 gene is reduced, and the low expression of the BHLHE22 gene is related to advanced pathological staging and poor prognosis. Meanwhile, experiments show that overexpression of the BHLHE22 can inhibit growth of tumor cells, and silence of the gene can promote malignant progression. Meanwhile, the deubiquitination enzyme OTUD3 stabilizes the BHLHE22 protein through the deubiquitination activity of the deubiquitination enzyme OTUD3, and the effect depends on the key C76 site of the deubiquitination enzyme OTUD3. In addition, the BHLHE22 inhibits a downstream target gene CDT1 through transcription to play an anti-proliferation function, and the effect can be reversed by CDT1 overexpression. The invention discloses the key cancer suppression effect of the OTUD3 / BHLHE22 / CDT1 signal axis in the TNBC, and provides a new potential target spot for the diagnosis and treatment of the TNBC.

This invention relates to a proximity nano-inducer for protein post-translational modification, its preparation method, and its application. The nano-inducer comprises gold nanoclusters and peptides modified on the surface of the gold nanoclusters. The peptides include peptides targeting target proteins and peptides targeting modifying enzymes. The nano-inducer obtained by this invention can effectively enter cells, induce post-translational modifications on specific proteins, and maintain a certain level of activity for at least 72 hours. It can induce O-GlcNAc glycosylation, ubiquitination, deubiquitination, phosphorylation, dephosphorylation, acetylation, or deacetylation of target proteins. Furthermore, the nano-inducer can specifically induce two different types of post-translational modifications on one target protein, or induce a specific post-translational modification on two different target proteins.

The invention discloses a rice deubiquitination enzyme gene OsZUFSP as well as cloning and application of the rice deubiquitination enzyme gene OsZUFSP. The OsZUFSP is a deubiquitination enzyme gene separated from rice, is composed of 1245 basic groups, and encodes a ZUFSP type deubiquitination enzyme with the molecular weight of 46 kDa and positioned in a cell nucleus and cytoplasm, namely the OsZUFSP. The OsZUFSP participates in the rice ubiquitination removal process and responds to the biological stress response of southern rice black-streaked dwarf virus invasion. The phenotypes of mutant rice with the OsZUFSP gene knocked out and over-expressed transgenic rice are not obviously different from those of wild rice, but the resistance of the mutant rice with the OsZUFSP gene knocked out to the southern rice black-streaked dwarf virus is enhanced, the symptoms of diseased plants are relieved, the susceptibility of the transgenic rice with the OsZUFSP gene over-expressed to the southern rice black-streaked dwarf virus is enhanced, and the resistance of the mutant rice with the OsZUFSP gene knocked out to the southern rice black-streaked dwarf virus is reduced. The symptom of the diseased plant is aggravated, which indicates that the OsZUFSP gene positively regulates and controls the southern rice black-streaked dwarf virus to infect rice Therefore, the gene can be knocked out through a gene editing technology to improve the resistance of the rice to the southern rice black-streaked dwarf virus.

This application discloses the use of deubiquitinase (CYLD) as a biomarker in the preparation of intervention products for late-onset sepsis in preterm infants. The intervention products are used to downregulate CYLD expression or deubiquitination activity to promote intestinal maturation in preterm infants and prevent the occurrence of late-onset sepsis. This application aims to address the challenge of preventing late-onset sepsis in preterm infants due to delayed development of the intestinal immune barrier. Through experiments conducted in three dimensions—mechanism verification, animal efficacy evaluation, and clinical model simulation—this application demonstrates the significant effect of CYLD-targeted intervention products in preventing late-onset sepsis in preterm infants. This invention provides a formulation that downregulates or inhibits the expression of CYLD, a negative immunomodulatory target, to actively induce the maturation of intestinal epithelial cells and strengthen the physical barrier in preterm infants.

The invention belongs to the technical field of medicines and disease treatment, and particularly relates to application of a substance for inhibiting expression of deubiquitinase in preparation of a product for treating pancreatic cancer. The invention provides application of a substance for inhibiting expression of deubiquitinating enzyme USP36 in preparation of a product for treating pancreatic cancer. The amino acid sequence of the deubiquitinating enzyme USP36 is as shown in SEQ ID NO. 1. The silent deubiquitinase USP36 is found to significantly inhibit the killing ability of pancreatic cancer cells to resist CD8 + T cells through deubiquitinase RNA interference library screening for the first time. Moreover, the USP36 is found to promote the deubiquitination of the YAP protein and stabilize the YAP protein, so that more YAP / TEAD is combined to an enhancer region of the PD-L1, the expression of the PD-L1 is promoted, and finally the immunity of pancreatic cancer cells is promoted.

The invention discloses application of dendrobium officinale exosomes in improvement of sepsis lung injury and pulmonary ischemia reperfusion injury, the dendrobium officinale exosomes are extracted, separated and purified by adopting an ultracentrifugation method, and the dendrobium officinale exosomes participate in improvement of the sepsis lung injury and the pulmonary ischemia reperfusion injury by regulating GPX4 dependent ferroptosis; specifically, by targeting alveolar epithelial cells, blocking GBP2-mediated OTUD5 ubiquitination degradation and stabilizing OTUD5 protein, the dendrobium officinale exosome enhances GPX4 deubiquitination protection of the dendrobium officinale exosome, maintains GPX4 activity, inhibits lipid peroxidation and ferroptosis, finally relieves the sepsis lung injury, and provides a new potential treatment strategy for the sepsis lung injury.