7 results about "Proteasome degradation" 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 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.

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 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.

The invention belongs to the technical field of biological medicines, and relates to application of a histone deacetylase inhibitor HDACi in preparation of a medicine for preventing and / or treating hyperammonemia-induced encephalopathy. According to the invention, a histone deacetylase inhibitor HDACi is used as a new medicine, the HDACi can enter a central nervous system, and the GS is triggered to be degraded through a proteasome mediated by CRBN E3 ubiquitin ligase by improving the acetylation level of a key enzyme, namely glutamine synthetase (GS), of astrocytes, so that the GS protein abundance is reversibly reduced, and the GS protein abundance is reduced. The application has the advantages that pathological accumulation of toxic metabolite glutamine can be reduced from the source, cerebral edema, autophagy-lysosomal dysfunction, neuroinflammation and neuron injury caused by the pathological accumulation can be synchronously improved, severe neurotoxicity such as persistent enzyme inhibition and acute epilepsy caused by irreversible inhibitors such as MSO can be avoided, clinical transformation risks can be obviously reduced, and the safety is high.

The present invention provides compounds that degrade Kirsten rat sarcoma viral oncogene homolog (KRAS) proteins, including mutant forms, through ubiquitination and subsequent proteasomal degradation of the KRAS protein. The compounds can be used to treat various cancers.

This invention discloses the application of a protein conjugate in membrane protein degradation and a method for membrane protein degradation. The protein conjugate comprises a carrier and an antibody; the antibody can be effectively conjugated to a multivalent antibody via the carrier; membrane protein degradation includes the protein conjugate mediating the cross-linking of the target protein to form aggregates, followed by degradation of the target protein via the proteasome and / or lysosome degradation pathways. This protein conjugate can effectively degrade membrane proteins, and throughout the process, it does not rely on degradation ligands targeting the proteasome or lysosome receptor, thus possessing strong applicability.