54 results about "Ubiquitin proteasome" patented technology

This invention is directed to the treatment of inflammatory and autoimmune diseases by administering proteasome inhibitors, ubiquitin pathway inhibitors, agents that interfere with the activation of NF-kappaB via the ubiquitin proteasome pathway, or mixtures thereof. The invention is further directed to the treatment of inflammatory and autoimmune diseases by administering an effective combination of a glucocorticoid and a proteasome inhibitor, ubiquitin pathway inhibitor, agent that interferes with the activation of NF-kappaB via the ubiquitin proteasome pathway, or mixture thereof. Pharmaceutical compositions comprising a combination of a glucocorticoid and a proteasome inhibitor, ubiquitin pathway inhibitor, agent that interferes with the activation of NF-kappaB via the ubiquitin proteasome pathway, or mixture thereof are also contemplated within the scope of the invention.

Restenosis of blood vessels after angioplasty is achieved by preventing of cell proliferation, particularly of smooth muscle cells, in blood vessel walls by inhibiting the ubiquitin-proteasome protein degradation pathway. The inhibition is accomplished by administering to the cells in the blood vessel walls a compound, e.g., a protein or small molecule, capable of inhibiting the ubiquitin-proteasome protein degradation pathway. The inhibiting compound is preferably administered by coating the compound on a stent and implanting the stent in the blood vessel after angioplasty.

Parkinson's disease is caused by the preferential loss of substantia nigra dopamine neurons. A Parkin Interacting Substrate, PARIS (ZNF746) is identified. The levels of PARIS are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human brain Parkinson's disease patients. PARIS represses the expression of the transcriptional co-activator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons that is PARIS dependent. Overexpression of PARIS causes selective loss of DA neurons in the substantia nigra, which is reversed by either parkin or PGC-1α co-expression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

The present invention describes novel uses for inhibitors of the ubiquitin proteasome degradative pathway. In particular it describes methods for improving cardiac function, increasing alpha myosin levels in the heart, and increasing SERCA levels in the heart. The invention also provides methods for treating cardiac hypertrophy through inhibiton of the ubiquitin proteasome.

Compounds of Formulas I-XLIII are identified as direct inhibitors of p97 ATPase or of the degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. Methods and compositions are disclosed for inhibiting p97 ATPase and the degradation of a p97-dependent UPS substrate, and for identifying inhibitors thereof.

The hypoxia inducible factor-1 (HIF-1) transcription factor is an important regulator of the cellular response to hypoxia. The activity of HIF-1 is regulated by the level of the HIF-1α subunit, HIF-1α, which is rapidly degraded under normoxic conditions by the ubiquitin-proteasome pathway. HIF-1α levels increase under hypoxic conditions. Many human cancers also show constitutively increased HIF-1α levels. PX-478 or S-2-amino-3-[4′-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride, is a novel anticancer agent, and is capably of decreasing both constitutive and hypoxia induced HIF-1α protein levels and HIF-1 transactivation in vitro and in vivo. In method embodiments, the administration of PX-478 is independent of the pathways of HIF-1α regulation involving the von Hippel-Lindau protein and p53. PX-478 causes an increase in polyubiquitinated HIF-1α levels due to inhibition of HIF-1α deubiquitination. The levels of other proteins whose proteasomal breakdown is mediated by ubiquitination are not affected by PX-478. Deubiquitination is a novel pathway for the regulation of cellular HIF-1α levels and PX-478 is a specific inhibitor of the pathway. Therapeutic compounds for regulating cellular HIF-1α levels and methods of regulating cellular HIF-1α levels are herein provided.

The invention relates to a prediction method for the ubiquitination degradation of a target protein. The prediction method comprises the following steps: A1, predicting the interaction of protein subunits by adopting a convolutional neural network method; A2, constructing a spatial three-dimensional structure of the ubiquitin marking system; A3, predicting a ubiquitination-degraded target protein,downloading a three-dimensional structure file of the target protein, complementing the three-dimensional structure of the target protein by using a homologous modeling method, and predicting the interaction between the target protein and a E3 ubiquitination marking system by using the convolutional neural network method; after that, optimizing an overall spatial three-dimensional structure of interaction between the E3 ubiquitin marking system and the target protein by adopting a molecular dynamics method, judging whether the target protein is possibly marked by the E3 ubiquitin marking system or not according to the stability of the system, and performing ubiquitin-target protein marking by virtue of the ubiquitin-target protein marking system, and degrading the protein by virtue of a ubiquitin-proteasome.

A polypeptide, the amino acid sequence of which comprises a sequence as set forth in SEQ ID NO:2, including at least one mutation within the degron domain of the polypeptide encompassed between positions 1 and 35 of the sequence, wherein said at least one mutation reduces the susceptibility of the polypeptide to ubiquitin-proteasome degradation.

The invention relates to an ubiquitin E1 inhibitor and a preparation method thereof. Series compound Y-1-benzene pyrazole silane-3,5-diketone and relevant derivative (such as 4-(4-ethyoxyl-3-methoxybenzylidene)-1-benzene pyrazole silane-3,5-diketone, and the like) with different alternative groups are prepared by a liquid-phase organic synthesis method according to the structure of PRY-41(4(4-(5-nitro-furan group-methylene]-3,5-dioxo-pyrazolidine-1-radical)-ethyl benzoate). The ubiquitin E1 inhibitor can be used for inhibiting protein degradation mediated by ubiquitination and nondegradation of ubiquitination, and can kill transformed cells containing p53 in the process of blocking up the NFkB activity by the inhibitor, that is to say, the inhibitor possibly has the potential property of treating tumor and can be used as an important tool for researching ubiquitin proteinase system mechanism.

The present invention provides cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway along with their use in therapeutic applications as described herein.

The invention discloses a derivative of a multi-target antitumor inhibitor, namely 2-aminopyrrole-triazine and a synthesis method thereof, and relates to the technical field of the treatment of abnormal cells in mammals. The derivative is synthesized by taking ethyl isocyanoacetate as a starting point through a chemical synthesis method, and has the advantages of mature process, short production period, environment friendliness, low cost and the like. The product can be used as a heat shock protein (Hsp) 90 multi-target antitumor inhibitor, can inhibit Hsp90, and promote the degradation of Hsp90 effect proteins which play an important role in tumor growth signal pathways through ubiquitination, so that multiple targets of the tumor growth signal pathways are blocked and the growth of tumor is effectively prevented. The derivative has higher affinity with tumor cells, can selectively kill the tumor cells, and promote the degradation of primer proteins thereof through ubiquitin-proteasome pathways, so that the effects of tumor treatment and resistance of the targets are achieved, and the derivative has strong action and small side effect.

A polypeptide, the amino acid sequence of which comprises a sequence as set forth in SEQ ID NO:2, including at least one mutation within the degron domain of the polypeptide encompassed between positions 1 and 35 of the sequence, wherein said at least one mutation reduces the susceptibility of the polypeptide to ubiquitin-proteasome degradation.

The invention discloses use of nitrine phlorizin (4-Az) as a key branching enzyme GGPPS inhibitor in an MVA pathway (mevalonate pathway), especially use in preparing a drug for treating non-alcoholicfatty liver disease. According to a series of experiments, the 4-Az can cause GGPPS protein to generate ubiquitin-proteasome pathway dependent degradation, has an inhibiting effect on GGPPS protein expression, and can be used as the inhibitor of GGPPS protein expression. More specifically, the nitrine phlorizin can reduce lipid accumulation and fatty degeneration of the livers, can reduce level ofglutamic-pyruvic transaminase and glutamic oxalacetic transaminase in blood, has the activity of protecting the liver function, and can be used for preparing the drug for treating the non-alcoholic fatty liver disease.

Reduced degeneration of an axon predetermined to be subject to degenerative neuropathy in a term patient is effected by contacting the axon in situ with an effective amount of a ubiquitin-proteasome system (UPS) inhibitor sufficient to reduce degeneration of the axon; and detecting a resultant reduction in the degeneration of the axon in situ.

The invention relates to a cDNA sequence, a coding protein, a full-length gene sequence and the clone method of a 26S proteinase body subunit RPT2 gene (DvRPT2)in Dunaliella viridis. The uplift expression of 26S proteinase body subunit RPT2 gene in Dunaliella viridis enhances the hydrolytic efficient of TP, accelerates that the substrate protein enters the active position of the proteinase body, reduces the abnormal protein content in the cell, and improves the salt resistance of Dunaliella viridis, so the research about Dunaliella viridis RPT2 subunit indicates the protein degradation pathway of 26S proteinase body, the salt endurance mechanism and the salt-resistance plant improvement, which has the finite theoretical and actual application value.

The invention relates to the finding that turnover of DISC1 (Disrupted in schizophrenia 1) is mediated by the F-box-containing protein FBXW7 (F-box / WD repeat-containing protein 7). The sequence within DISC1 that binds to FBXW7 and targets DISC1 for turnover by the ubiquitin-proteasome system is identified. The invention provides antagonists that inhibit this interaction and methods of using these antagonists to decrease DISC1 turnover, for example in treatment of neuropsychiatric disorders, as well as methods of identifying new antagonists.

The invention discloses a medicine that cures muscle atrophy after spinal cord injury and its application method: the medicine that cures muscle atrophy after spinal cord injury is losartan. The application method is that losartan activates a signal pathway of IGF1 / Akt / mTOR and inhibits an expression of MuRF-1; A receptor blocking pharmacon of angiotensin II takes effect through activating the pathway of IGF-1 / Art / mTOR and inhibiting a ubiquotin-proteasomes system. The receptor blocking pharmacon of angiotensin II can improve the skeletal muscle atrophy after spinal cord injury of rats and may take effect through activating the pathway of IGF-1 / Akt / mTOR and inhibiting the ubiquitin-proteasomes system, which provides a part of basis for later clinical application and combined therapy.

Reduced degeneration of an axon predetermined to be subject to degenerative neuropathy in a term patient is effected by contacting the axon in situ with an effective amount of a ubiquitin-proteasome system (UPS) inhibitor sufficient to reduce degeneration of the axon; and detecting a resultant reduction in the degeneration of the axon in situ.

The invention relates to the field of 26S proteasome inhibition, activation and modulation and to identify compounds which activate 26S proteasome in live cells and a method of treating autoimmune diseases, cancer, inflammation and neurogenerative disorders by inhibition, activation and modulation of the 26S proteasome.

The invention relates to compositions for the prophylaxis and / or treatment of viral infections, in particular of infections with influenza viruses which cause influenzal infections. The invention relates to compositions which comprise inhibitors of the ubiquitin-proteasome system, in particular proteasome inhibitors, as active ingredients. The present invention further relates to the systemic and topical, preferably the aerogenic administration of proteasome inhibitors. The active substance employed according to the invention as proteasome inhibitor can be employed with at least one further substance having antiviral activity for the prophylaxis and / or therapy of influenzavirus infections.

The present invention relates to generating hiPSC-derived cardiomyocytes and embryoid bodies that recapitulate the disease phenotype of Long QT Syndrome and their use in developing pharmacological treatments thereof. The present invention also includes the use of a compound which inhibits the ubiquitin-proteasome pathway for the preparation of a medicament for the prophylaxis or treatment of a disease associated with prolonged ventricular repolarization (cardiac arrhythmia) caused by one or more mutations in the amino acid sequence of the hERG potassium channel.

The present invention provides an inhibitor of intracellular protein degradation for use in the treatment and prevention of muscular dystrophy in a mammal. In particular, the invention provides an autophagy inhibitor and / or an inhibitor of the ubiquitin-proteasome system (such as a proteasome inhibitor) for use in the treatment and prevention of muscular dystrophy (such as congenital muscular dystrophy [e.g. MDC1A) and Duchenne muscular dystrophy [DMD]). The invention further provides corresponding methods of treatment and prevention of muscular dystrophy.

The invention relates to a composition with an aging delaying effect and a skin care product thereof. The composition comprises the following components: a pumpkin seed extract and an olive leaf extract. The composition provided by the invention achieves the purpose of delaying senescence by activating mitochondrial autophagy and ubiquitin-proteasome activity and through the synergistic effect of the mitochondrial autophagy and ubiquitin-proteasome activity. When the composition is added to a skin care product and applied to skin, cell waste such as aged and damaged mitochondria and damaged protein can be timely removed from the skin, cell renewal is accelerated, cell apoptosis is reduced, and thus skin aging caused by endogenous and exogenous factors is delayed.