27 results about "Deubiquitinating enzyme" patented technology

The present disclosure provides, inter alia, a recombinant engineered deubiquitinase (DUB) and methods for treating or ameliorating an inherited ion channelopathy, such as long QT syndrome, Brugada syndrome, or cystic fibrosis, in a subject. Further provided are methods for screening mutations causing such inherited ion channelopathies for a trafficking-deficient mutation that is treatable by the recombinant engineered DUB disclosed herein.

The present disclosure provides, inter alia, an engineered molecule and methods for treating or ameliorating an inherited ion channelopathy, such as Brugada syndrome, or Dravet syndrome, in a subject. Further provided are methods for regulating an ion channel density and ion influx thereof by the engineered molecule disclosed herein.

The invention relates to the technical field of medical compounds, in particular to a deubiquitinating enzyme targeted chimera compound as well as a pharmaceutical composition and application of the deubiquitinating enzyme targeted chimera compound. The deubiquitinating enzyme targeting chimera compound is a compound with a structure as shown in a formula (I), and / or a pharmaceutically acceptable salt thereof, and / or a racemic mixture, a hydrate, a solvate, a prodrug, an enantiomer, a diastereoisomer and a tautomer thereof, the structural formula of the formula (I) is as shown in the specification, and the definitions of X, Linker and cGAS Ligand are as shown in the specification. The compound provided by the invention increases the abundance of the cGAS protein, has an obvious effect of improving the stability of the intracellular cGAS protein, and is used for preparing medicines for treating inflammatory diseases, tumors, cardiovascular and cerebrovascular diseases and infectious diseases.

The invention relates to a deubiquitination enzyme Fc fusion protein, a product thereof, a preparation method and application thereof in Miao compound screening, and belongs to the technical field of fusion proteins. The technical problem to be solved is that OTUD3 protein is unstable and easy to degrade in the prior art; according to the key point of the technical scheme, the OTUD3 and Fc fusion protein is provided, and the fusion protein is easy to purify while maintaining the activity of OTUD3 and can be applied to screening of Miao compounds.

The invention belongs to the field of medicinal chemistry, and discloses a deubiquitinating enzyme USP28 small-molecule inhibitor and a preparation method and application thereof, the general formula of the deubiquitinating enzyme USP28 small-molecule inhibitor is as follows: in the formula, A ring is selected from substituted or non-substituted C5-6 aromatic ring; an indole ring; 2, 4, 5-benzothiazole ring; and a substituted or non-substituted C5-6 aromatic heterocyclic ring, wherein a heteroatom is selected from N, O or S. R1 is selected from hydrogen, nitryl, hydroxyl and halogen; the compound is selected from the group consisting of phenyl, phenyl, phenyl, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, phenylamino, r < 2 > is selected from tetrahydroisoquinolyl or tetrahydroisoquinolyl substituted by one or more halogens or methyl groups, phenyl-N, N-dimethyl methylamino, N-methyl phenyl methylamino, methyl tetrahydropyridoxyl, N, N-dimethyl methylaniline or N, N-dimethyl naphthyl amino or N, N-dimethyl halogenated anilino, R < 2 > is selected from tetrahydroisoquinolyl or tetrahydroisoquinolyl substituted by one or more halogens or methyl groups, phenyl-N, N-dimethyl methylamino, N-methyl phenyl methylamino, methyl tetrahydropyridoxyl, N, N-dimethyl methyl anilino or N, N-dimethyl naphthyl amino or N, N-dimethyl halogenated anilino. The compound shows good selective inhibitory activity on USP28 enzyme, and has a good application prospect when being used as an active component for preparing USP28 inhibitor drugs.

The invention discloses application of a deubiquitinating enzyme STAMBPL1 as a pancreatic cancer diagnostic kit and in targeted drug development. According to the research, by mining a TCGA-PAAD public data set of a TCGA database, the transcriptome expression level of STAMBPL1 in pancreatic cancer tissue is found to be remarkably higher than that in normal tissue. The research also finds that the proliferation and migration of the human pancreatic cancer cell line PANC-1 can be inhibited in vitro by knocking down the STAMBPL1 through the small interfering RNA, and the mRNA level expression quantity of tumor proliferation and cell cycle related genes is reduced. According to the expression difference of the STAMBPL1 in pancreatic cancer derived from a patient and normal tissue and the experimental results of cell phenotype and gene transcription level expression detection after knockdown, the STAMBPL1 can be possibly used as a potential biomarker of pancreatic cancer and a potential target of a pancreatic cancer diagnostic kit.

The invention discloses application of a deubiquitinating enzyme inhibitor and an OTUD7A-HINT1-mTOR axis in regeneration of a central nervous system, and belongs to the technical field of biology. The technical problem to be solved by the invention is how to promote the regeneration of the central nervous system. The invention finds that the deubiquitinating enzyme inhibitor PR-619 can promote the growth of axons in neuron cultures and retina explants, protect the survival of RGCs and enhance the regeneration of axons after ONC. The PR-619 can also promote CNS regeneration by down-regulating expression of HINT1, HINT is one of main targets of the PR-619 and plays a role through an mTOR signal channel, and OTUD7A serves as an upstream regulation factor of the HINT1. The PR-619 can be used for treating the CNS injury, the OTUD7A-HINT1-mTOR axis can be used as a CNS injury treatment target, and the PR-619 and the OTUD7A-HINT1-mTOR axis can be combined for treating the CNS injury.

The application of the deubiquitinase to the immune reconstitution incomplete prediction target of the AIDS patient comprises the following steps: identifying that the ubiquitinase is YOD1 and has obvious interaction with HIV virus protein Nef; identifying that the YOD1 stabilizes the HIV auxiliary protein Nef through the protein level instead of the RNA level; identifying that the YOD1 can prolong the half-life period of the HIV auxiliary protein Nef; the YOD1 is identified to enhance the expression level of Nef in virus particles of an HIV NL4-3 clone strain by reducing the ubiquitination of the Nef protein of HIV-1 (Human Immunodeficiency Virus 1) and influence the ubiquitination of the K6 site of the Nef protein; identifying that YOD1 inhibits ubiquitination of Nef protein and stabilizes the Nef protein; yOD1 is identified to be in positive correlation with Nef under the HIV infection condition, and the positive correlation is increased along with the increase of the infection dose or the infection time; it is identified that YOD1 promotes virus replication by stabilizing the Nef protein level and aggravates loss of CD4 + T cells, and the expression level of YOD1 is in positive correlation with immune imperfection of an HIV-1 infected person; it is identified that the vitamin C can effectively lower the expression level of YOD1 and Nef protein, and then the virus virulence is reduced.

The invention discloses application of EIF3H in treatment of liver cancer. Research finds that MASH and hepatic fibrosis can be relieved by down-regulating fatty acid de novo synthesis of EIF3H, and tumorigenesis in an HCC mouse model induced by DEN + HFHC and HDTI + HFHC is inhibited. In mechanism, EIF3H is combined with FASN, and KEAP1 mediated FASN ubiquitination is antagonized, so that the FASN protein is stabilized. Therefore, EIF3H is a FASN deubiquitinase which is not illuminated previously, and drives the MASLD-HCC process by promoting fatty acid metabolism reprogramming. The EIF3H-FASN axis can be used as a therapeutic target of liver cancer.

The invention discloses an application of luwuaconitine in preparation of a medicine for treating hepatic fibrosis. The invention firstly proposes and verifies that the luwulinine can effectively improve fibrosis symptoms of mice with hepatic fibrosis and recover related functions of the liver; meanwhile, the treatment effect can be further improved by combining the deubiquitinating enzyme inhibitor, and a new direction is provided for treatment of hepatic fibrosis.

The invention belongs to the field of biological medicine, and particularly relates to application of a targeted JOSD1 inhibitor in preparation of tumor treatment drugs. Researches find that deubiquitinating enzyme JOSD1 is highly expressed in HCC and is closely related to poor prognosis of a patient. The JOSD1 stabilizes PGAM1 protein on a key lysine site by regulating ubiquitination-lactic acid post-modification (PTM) interaction of a glycolysis key enzyme PGAM1, enhances the enzymatic activity and lactic acid generation of the PGAM1 protein, and promotes glycolysis metabolism and malignant progression of tumor cells. The accumulation of lactic acid causes infiltration and function inhibition of CD8T cells, so that an immunosuppressive tumor microenvironment is formed. Targeted inhibition of JOSD1 can significantly reduce the proliferation and transfer ability of HCC cells and recover immune response. Animal experiments show that the liver-specific JOSD1 inhibitor can effectively inhibit tumor progression and has a remarkable synergistic effect with anti-PD-1 immunotherapy, and the lifetime is prolonged.

The present invention relates to hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carbonitriles with activity as inhibitors of the deubiquitylating enzyme USP30, having utility in a variety of therapeutic areas, including conditions involving mitochondrial dysfunction, cancer and fibrosis.

The present invention relates to a class of N-cyanopyrrolidines of formula(I) with activity as inhibitors of the deubiquitylating enzyme USP30, having utility in a variety of therapeutic areas, including cancer and conditions involving mitochondrial dysfunction.

The application belongs to the technical field of molecular marker assisted breeding, and particularly relates to a corn chromosome 4 white spot disease resistance related molecular marker and application, specifically, the application provides a corn white spot disease resistance related molecular marker, the molecular marker gene is a Zm00001eb168510 gene and / or a sequence as shown in SEQ ID NO:1, a CDs sequence of the Zm00001eb168510 gene is as shown in SEQ ID NO:2, through years of experiments in multiple points, the application is co-located to a white spot disease resistance QTL qMWS4-4 interval and a resistance SNP:4-14146725 and an associated gene Zm00001eb168510 on a corn chromosome 4, the SNP site can be located in different environments through QTL linkage analysis and GWAS correlation analysis, and can explain 15.14% of the phenotype variation; the associated candidate functional gene mainly encodes a cysteine protease superfamily protein, the cysteine protease superfamily contains a deubiquitinating enzyme, and plays an important role in plant development and adversity response.

This invention discloses a thiazole compound, a deSUMO and / or deubiquitinase inhibitor, its preparation method, and its application, belonging to the technical fields of molecular biology and biomedicine. The thiazole compound has the structure shown in Formula E, wherein R is selected from one of C1-5 alkyl, heterocyclic alkyl, benzoheterocyclic, substituted piperidine, substituted piperazine, phenyl, benzyl, or H, and A is selected from one of a benzene ring, piperidine, or hydrogen. Furthermore, this invention also provides a method for synthesizing the above-mentioned thiazole compound. Additionally, this invention provides a deSUMO and / or deubiquitinase inhibitor, which is one or more of the above-mentioned thiazole compounds. Furthermore, this invention provides the application of the above-mentioned deSUMO and / or deubiquitinase inhibitor in the preparation of a drug that inhibits the activity of deSUMO and / or deubiquitinase. This thiazole compound can effectively inhibit the activity of DESI2 enzyme.

The invention relates to application of pamidronate in preparation of a medicine for preventing, relieving and / or treating non-small cell lung cancer. According to the application, new application of the pamidate is found, that is, the pamidate can inhibit the growth of the non-small cell lung cancer resistant to the tyrosine kinase inhibitor EGFR-TKIs, which indicates that the pamidate can be applied to the preparation of the medicine for preventing, relieving and / or treating the non-small cell lung cancer. As an inhibitor of the deubiquitinating enzyme USP20, the compound can target the deubiquitinating enzyme USP20, reverses the drug resistance of non-small cell lung cancer to a tyrosine kinase inhibitor, and plays a synergistic anti-tumor role with the tyrosine kinase inhibitor.

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 discloses application of OTUD4 as a pancreatic adenocarcinoma (PAAD) treatment target, and belongs to the field of biological medicine. A large number of experiments prove that OTUD4 is highly expressed in PAAD tissue and is related to poor prognosis. In mechanism, OTUD4 interacts with YAP protein, and multi-ubiquitination connected with K48 of YAP is reduced through the activity of ubiquitination enzyme of OTUD4, so that the YAP protein is stabilized, a Hippo / YAP signal axis is activated, and PAAD progress is promoted. The inhibition of OTUD4 can down-regulate the activity of YAP, inhibit the proliferation, migration and invasion of pancreatic cancer cells, and induce apoptosis. The invention provides application of an OTUD4 inhibitor in preparation of a medicine for treating pancreatic cancer and a related diagnosis and screening method.

The application discloses a deubiquitinating enzyme Fc fusion protein and application thereof in lead compound screening, and belongs to the technical field of fusion proteins. The technical problem to be solved is that OTUD3 protein is unstable and easy to degrade in the prior art. The technical solution is characterized in that an OTUD3 and Fc fusion protein is provided, the fusion protein is easy to purify while maintaining the activity of OTUD3, and can be applied to lead compound screening.

The present disclosure provides, inter alia, a recombinant engineered deubiquitinase (DUB) and methods for treating or ameliorating an inherited ion channelopathy, such as long QT syndrome, Brugada syndrome, or cystic fibrosis, in a subject. Further provided are methods for screening mutations causing such inherited ion channelopathies for a trafficking-deficient mutation that is treatable by the recombinant engineered DUB disclosed herein.

The present invention relates to a class of N-cyanopyrrolidines with activity as inhibitors of the deubiquitylating enzyme USP30, having utility in a variety of therapeutic areas, including conditions involving mitochondrial dysfunction, cancer and fibrosis: (formulae (I)(i) and (I)(ii)).

The application discloses application of USP33 in stabilizing HDAC3 in tumors, and relates to the technical field of biological medicines; the USP33 improves the protein stability of HDAC3 and promotes the progress of liver cancer. The application finds and clarifies that in hepatocellular carcinoma, the deubiquitinating enzyme USP33 promotes the proliferation of liver cancer by stabilizing the protein level of HDAC3; the application discloses a pathway for the synergistic regulation of liver cancer progress by USP33-HDAC3; the application proposes a strategy for targeting the signal shaft to treat hepatocellular carcinoma; by inhibiting the expression of USP33 or directly inhibiting the activity of HDAC3, the degradation of HDAC3 or the blocking of the function of HDAC3 can be promoted, so that the purpose of inhibiting the growth of tumors is achieved; and the application provides a new candidate target point for the drug research and development of hepatocellular carcinoma.

The invention discloses application of visceral fat-derived UCHL5 as a myocardial fibrosis biomarker and a drug target, and belongs to the technical field of cardiovascular disease detection, prevention and treatment. From the perspective of fat-cardiac axis, it is proved for the first time that deubiquitinating enzyme UCHL5 from visceral fat (VAT) and entering circulation is a key promoting factor of angiotensin II (Ang II) related myocardial fibrosis, and it is proved that UCHL5 can be used as a body fluid biomarker for monitoring myocardial fibrosis and also is an anti-fibrosis target with medicinal properties. On the basis, UCHL5 can be applied to diagnosis, prevention and treatment of myocardial fibrosis as a biomarker and a drug target of myocardial fibrosis.

The invention discloses a ubiquitin probe targeting deubiquitination enzyme hyposulfonic acid and a preparation method and application thereof, the structural general formula of the ubiquitin probe is Biotin-Ub-W, Ub is a ubiquitin molecule; w is a nucleophilic warhead group, can be specifically subjected to a covalent reaction with a hyposulfonic acid (-SOH) functional group formed by cysteine at an active site of DUBs under oxidative stress, and has no reactivity on reduced cysteine (-SH). The method can be used for specifically marking, enriching and identifying the DUBs regulated and controlled by redox in a cell or tissue sample, provides an unprecedented tool for researching the functions of the DUBs in related diseases such as cancers and neurodegenerative diseases, and can be used for screening drugs targeting the specific state.

The invention further discloses application of the deubiquitinating enzyme USP2 serving as a target spot to screening or preparation of drugs for preventing and / or treating depression. The invention belongs to the technical field of medicines, and relates to application of USP2 serving as a target spot in screening or preparing medicines for preventing and / or treating depression. The invention provides an effect and a mechanism of deubiquitinating enzyme USP2 in corticosterone-induced depression. Experiments prove that USP2 overexpression can improve depression-like behaviors by protecting neurons, promoting neurogenesis and inhibiting overexpression of microglial cells and neuroinflammation. The USP2 can be used as a target spot to screen or prepare a medicine for preventing and / or treating depression.

This invention discloses a target for treating autoimmune diseases and its application, belonging to the field of cell biology. This invention discovers that a deubiquitinating enzyme, as shown in the amino acid sequence of SEQ ID NO.1, can be effectively targeted to inhibit host lupus-like inflammation and tissue damage. Simultaneously, this invention reveals a novel use of ubrogepant in the treatment of autoimmune diseases. The results of this invention can provide new targets and ideas for the development of drugs for treating autoimmune diseases, and can also be directly applied to the research field to guide the development of commercial products such as OTUD1-based chemical inhibitors and peptides.

The application discloses application of OTU4 genes or proteins coded by the genes in improving the high-temperature stress resistance of plants. The application discloses for the first time the influence of a new plant peroxisome protein coded by the OTU4 gene on the heat resistance of plants, and the mutation of the OTU4 gene causes the root growth defect of plants under high temperature. The application discloses for the first time the deubiquitinating enzyme in the peroxisome, and provides a theoretical basis and material support for the ubiquitination research in the peroxisome. The application provides a new gene resource and theoretical guidance for deepening the peroxisome function research and the research and application of the heat resistance of plants and the like.