60 results about "Proteasome Pathway" patented technology

The invention discloses a composition for treating diseases through protein degradation in a novel degradation way, and relates to the technical field of medicines. Comprising a mandolin-based androgen receptor degradation chimeric peptide (MbTACs), the mandolin-based androgen receptor degradation chimeric peptide (MbTACs) contains a targeting module YLCSSNNRERDKFRR combined with AR and a module combined with midnolin, a KLVFF sequence and a cell penetrating peptide PKKKPKV are added to the C end of the peptide, and a polypeptide molecule MbAD is formed. According to the invention, a midnolin-based MbTACs platform is developed, and the midnolin-based MbTACs platform is used for degrading specific proteins. The bifunctional molecules form a midnolin-MbTACs-target protein ternary complex between the target protein and the midnolin, and then the protein is degraded through a midnolin-proteasome way. The MbTACs can effectively degrade c-Myc and androgen antibodies in vitro and in vivo, and play an anti-tumor role. The MbTACs molecule represents a first midnolin-based target chimera, and the MbTACs molecule represents a first midnolin-based target chimera.

Disclosed in the present invention are a new recruitment element for a ubiquitin ligase and the use thereof, such as the use thereof in the preparation of a drug for targeted protein degradation, comprising a PROTAC drug. The inventors of the present invention creatively found a compound that recruits, by means of interaction with NCL, a ubiquitin ligase MDM2, and it is found by means of further experiments that the compound can serve as a new recruitment element for MDM2 and can be used in the preparation of a targeted protein degrader and other aspects. According to the above findings, the inventors prepared a targeted protein degrader, and found, by means of experiments, that the prepared targeted protein degrader can effectively mediate the degradation of a target protein by means of the ubiquitin-proteasome pathway, thereby achieving the treatment of target protein-related diseases (such as tumors), which has very good application prospects in the medical field.

The invention provides an L protein mutated recombinant foot-and-mouth disease virus strain and application thereof in vaccine preparation, and belongs to the technical field of biological medicine. Firstly, it is found that overexpression of CISD2 protein in host cells can inhibit FMDV replication, and an inhibition mechanism is analyzed, specifically, the CISD2 inhibits FMDV replication by inhibiting expression of L protein, especially inducing degradation of the L protein through a proteasome pathway. The invention also identifies a key site for degrading the L protein by the CISD2 protein, the recombinant foot-and-mouth disease virus with the mutated key amino acid site of the L protein is successfully constructed and rescued by introducing amino acid mutation of the key site into the L protein by utilizing a reverse genetic technology, the capabilities of degrading the L protein and inhibiting FMDV replication by the CISD2 protein are eliminated, the virus titer is improved, and the recombinant foot-and-mouth disease virus can be used for preparing the recombinant foot-and-mouth disease virus with the mutated key amino acid site of the L protein. The strain has good production performance and can be used for preparing recombinant foot-and-mouth disease virus strains and recombinant vaccine strains.

The invention discloses a novel EGFR (epidermal growth factor receptor) degradation agent as well as a preparation method and application thereof. The EGFR degradation agent is PROTAC with GROs (such as AS1411) as an MDM2 recruitment element, target protein EGFR and E3 ubiquitin ligase MDM2 can be pulled close in vivo, so that the EGFR is labeled with ubiquitin, and then the EGFR is degraded through a ubiquitin-proteasome pathway. Experiments show that the EGFR degradation agent can effectively degrade EGFR and generate corresponding curative effects (such as inhibition of tumor cell proliferation and promotion of tumor cell apoptosis), and has very good application prospects and research values. In addition, the inventor also finds that AS1411 can specifically target and penetrate a hematoma barrier, and can be used for in-vivo imaging, diagnosis and detection of brain tumors.

The application belongs to the technical field of biological medicine, and specifically discloses a compound for targeted degradation of fatty acid synthase and application thereof, which has a structure shown in general formula I or a pharmaceutically acceptable salt thereof. The compound provided by the application is designed through a target ligand-connection bridge-E3 ligand structure, realizes efficient degradation, can significantly reduce the level of FASN in high-expression cells, and thus specifically targets cells related to abnormal lipid metabolism. The mechanism of action depends on the ubiquitin-proteasome pathway and is time-dependent. The compound provided by the application has good biological activity of degrading FASN, can be applied to the development of anti-liver cancer drugs, and has a wide application prospect.

According to the application of the E3 ligase UFL1 modified by the Especially in clearing the SHBs / HBsAg, the SHBs / HBsAg can be cleared by inhibiting the expression of the E3 ligase UFL1 modified by the Especially, so that the effect of treating HBV infection or HBV related diseases is achieved. The strategy of the invention is to directly target and remove the existing SHBs / HBsAg protein, and the action is more direct and rapid. According to the present invention, the inherent protein mass control system (proteasome pathway) of cells is utilized, such that the high biocompatibility and the low off-target toxicity can be provided; and the combination of the strategy and the existing antiviral drugs is expected to further significantly improve the functional cure rate of hepatitis B.

The invention provides a recombinant foot-and-mouth disease virus strain with high antigen yield as well as a construction method and application thereof, and belongs to the technical field of biology. The invention relates to a recombinant foot-and-mouth disease virus strain, wherein L protein is mutant L protein with 108th amino acid mutated or deleted. According to the invention, overexpression of host protein RAB20 inhibits replication of FMDV, and L protein is degraded through a proteasome pathway, so that virus replication is inhibited; a recombinant foot-and-mouth disease virus strain which is not inhibited by host protein RAB20 to replicate is constructed by mutating a key amino acid site (108) in FMDV L protein, the recombinant virus can be stably passaged, has the characteristic of high virus titer on BHK-21 cells, improves the virus titer and antigen yield, can be used for preparing FMDV vaccines, and can be used for preparing FMDV vaccines. Good application prospects are realized.

The invention discloses ICA1L derived peptide and application thereof in relieving Alzheimer disease A beta pathology. The amino acid sequence of the ICA1L derived peptide is shown as SEQ ID NO.01. The invention further discloses a preparation method of the ICA1L derived peptide. The compound can be combined with low-density lipoprotein receptor associated protein 1 (LRP1), inhibit K48 connection type ubiquitination of the LRP1 and prevent degradation through a proteasome pathway, so that the protein level of the LRP1 is stabilized, and the expression of beta-site APP lyase 1 is reduced to reduce the generation and deposition of beta-amyloid protein. In vitro, the peptide shows good biocompatibility and cell uptake ability; in vivo, the peptide has blood-brain barrier permeability, can be positioned in neurons, can significantly reduce hippocampus and cortex A beta plaque deposition in a 5xFAD mouse model through caudal vein injection, reduces BACE1 and beta-CTF levels, and improves the cognitive function. The invention further discloses an ICA1L-LRP1 regulatory axis, and a new strategy is provided for treatment of the Alzheimer's disease.

This invention discloses a drug targeting the CK1ε gene or protein for treating duveliximab intestinal toxicity, belonging to the field of pharmaceutical technology. The drug reverses duveliximab intestinal toxicity by downregulating CK1ε gene expression, inhibiting CK1ε protein function, or inhibiting CK1ε protein accumulation. This invention provides a novel therapeutic drug target for intervening intestinal toxicity caused by duveliximab. This invention proposes that the E3 ubiquitin ligase NEDD4L can ubiquitinate CK1ε and subsequently degrade it through the ubiquitin-proteasome pathway, providing a new direction for current intervention strategies for drug-induced intestinal toxicity and addressing, to some extent, the current situation of limited available intervention drugs and their singular mechanisms. The intervention drug reverses duveliximab intestinal toxicity by downregulating CK1ε, expanding the clinical application value of duveliximab.

The present invention discloses a colorectal cancer radiotherapy sensitizing drug and its application, belonging to the field of biomedicine, and specifically relates to a colorectal cancer radiotherapy sensitizing drug, comprising a pharmaceutical active ingredient and a solvent, wherein the pharmaceutical active ingredient comprises doxorubicin and a nitrogen-containing compound, wherein the nitrogen-containing compound comprises quinoline-6-carbohydrazide and N-benzyloxymethyl-4-nitroimidazole. The colorectal cancer radiotherapy sensitizing drug disclosed in the present invention focuses on FOXP4, a key driver gene of colorectal cancer radiotherapy resistance, and degrades FOXP4 protein through the ubiquitin-proteasome pathway. This not only significantly increases the sensitivity of tumor cells to radiotherapy, inhibits tumor growth, and reduces damage to normal tissues; it also effectively circumvents the drug resistance problem that is prone to occur with traditional methods, significantly reduces R&D costs, accelerates clinical transformation, and has good clinical application prospects.

The invention discloses an anti-tumor pharmaceutical composition and application thereof, the pharmaceutical composition comprises cannabidiol and paroxetine hydrochloride, and the mass ratio of the cannabidiol to the paroxetine hydrochloride is (5: 1)-(20: 1). Research finds that cannabidiol and paroxetine hydrochloride can respectively reduce expression of PD-L1 on a tumor cell membrane through different mechanism ways, specifically, CBD promotes degradation of PD-L1 through a lysosome way; the PAR is used for promoting the degradation of the PD-L1 through a ubiquitin-proteasome way. Based on the discovery, the CBD and the PAR are further combined for use, and the result shows that compared with independent use of the CBD and the PAR, the combined use of the CBD and the PAR can play a synergistic anti-tumor role, and the CBD and the PAR have no obvious toxic and side effects and are relatively high in use safety.

The invention provides a BRD4 protein degradation agent and application thereof, and particularly provides a compound with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can degrade BRD4 protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the BRD4 protein. Wherein each group in the formula (I) is defined in the specification.

The invention relates to the technical field of biological medicine, and discloses a binding peptide targeting a C-terminal structural domain of human AARS1 protein and application, the binding peptide comprises an amino acid sequence represented by a general formula (I) and a Val-Ala-Xaa-Xaa-Arg-His core motif, and can specifically bind to the C-terminal structural domain of the human AARS1 protein. The binding peptide and the derivative thereof block an AARS1 mediated protein lactic acid modification signal channel by inhibiting the activity of AARS1 lactoacyltransferase or inducing protein degradation through a ubiquitin-proteasome pathway. The binding peptide provided by the invention avoids an N-terminal catalytic activity center of AARS1, does not influence the protein synthesis function of normal cells while exerting antitumor activity, has relatively high affinity and safety, and can be used for preparing drugs for treating AARS1 mediated diseases such as pancreatic cancer or a diagnostic reagent for detecting AARS1.

The application discloses application of an alkaloid derivative or a medicinal salt thereof in preparation of a medicine for resisting non-small cell lung cancer cisplatin resistance, and a structure of the alkaloid derivative is as follows: The application finds that compound A45 can induce K48 connection type polyubiquitination of TNKS, and is degraded through a proteasome pathway, triggers a DNA damage response, activates a p53 pathway, and induces autophagic cell death, so that a specific action mechanism is achieved to achieve a treatment effect of resisting non-small cell lung cancer cisplatin resistance. Therefore, the compound A45 can be used as a candidate compound for the non-small cell lung cancer cisplatin resistance, a major treatment dilemma, has important development prospects and clinical application value, and provides a scientific basis and an experimental basis for development of an antitumor effect of other Aaptamine alkaloid derivatives and exploration of a strategy for overcoming the non-small cell lung cancer cisplatin resistance.

The present invention belongs to the field of biomedicine and relates to a method for designing a vaccine with enhanced antigen presentation effect, which is mainly applied to the design and preparation of structural sequences of nucleic acid, protein, and polypeptide vaccines. In the present invention, a target antigen and a ligand, such as a polypeptide or protein domain having the function of binding or recruiting E3 ubiquitin ligase, are both encoded in the same nucleic acid sequence. After the nucleic acid molecule enters the cell, fusion expression of the antigen protein and the E3 ubiquitin ligase ligand is achieved, which promotes degradation of the antigen protein via the proteasome pathway, increases the number and abundance of antigen peptides containing the antigen epitope, forms more peptide-MHC (p-MHC) complexes, and is thus presented on the cell surface, enhancing the subsequent immune response and exerting efficient tumor immunotherapy. The nucleic acid, protein, and polypeptide vaccines provided by the present invention have efficient antigen presentation effect and strong immunogenicity, and have good prospects for clinical application.

The present invention relates to an inhibitor of heat shock protein 90, and discloses a bivalent inhibitor based on heat shock protein 90, a preparation method, and an application thereof. The compound has a structural formula as shown in Formula I: A-L-B Formula I, or a pharmaceutically acceptable salt, solvate, or optical isomer thereof, wherein A and B are ATP inhibitors of heat shock protein 90, and the motif structure of L is a flexible linking group of PEG and alkane, or a rigid linking group having an aryl, heteroalkyl, or heteroaryl group. The bivalent inhibitor can effectively inhibit the activity of the molecular chaperone protein HSP90, hinder the folding and modification of substrate proteins, degrade substrate proteins through the ubiquitin-proteasome pathway, induce non-native dimerization of HSP90, and interfere with protein-protein interactions associated with HSP90. At the same time, it also reduces the heat shock effect caused by HSP90 inhibition, and exhibits potent activity in degrading substrate proteins.

The present disclosure provides a light chain variant of botulinum toxin type E, in which a specific lysine residue is substituted with arginine. The light chain variant of botulinum toxin type E according to the present disclosure exhibits a significantly increased in vivo half-life due to the suppression of degradation via the ubiquitin-proteasome pathway.

The invention discloses a targeted protein degradation agent utilizing a ubiquitin-proteasome pathway as well as a preparation method and application of the targeted protein degradation agent, and belongs to the technical field of biological medicines. On the basis of a PROTAC (protein targeted degradation chimera) strategy and on the basis of imatinib, different Linkers are introduced to be connected with an E3 ubiquitin enzyme ligand Nutlin-3 derivative, a degradation tag is labeled on BCR-ABL cancer protein, and the degradation agent with the Bcr-Abl protein targeting capacity is constructed. A Western blot experiment shows that the targeted protein degradation agent shows a good degradation effect on the Bcr-Abl protein in K562 cells, and the compound WP shows a degradation effect on concentration dependence and time dependence of the Bcr-Abl protein. Tumor cell proliferation experiments show that the compound has certain inhibitory activity on K562 cells. Wherein when the Linker is dodecane-1, 12-diketone, the anti-proliferative activity is the best. An apoptosis experiment and a period experiment show that the targeted protein degradation agent can realize concentration-dependent promotion of cell apoptosis and retard cells in S and G1 / G0 periods.

This disclosure provides certain bifunctional compounds that induce the degradation of cyclin-dependent kinase 2 (CDK2) via the ubiquitin-proteasome pathway, and are therefore intended for the treatment of CDK2-mediated diseases. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided.

The present invention discloses an intelligent responsive fusion polypeptide (HPVP-02) targeting HPV E6 / E7 protein and its application in the treatment of cervical cancer. The amino acid sequence of the polypeptide is shown in SEQ ID NO.1. It is composed of a dual-targeting module (specifically binding to HPV E6 / E7 protein), a pH response module (H5E5 sequence), an immune activation module (PD-1 / PD-L1 inhibitory peptide) and a self-assembly module (amphiphilic nanostructure), and each module is connected in series through a flexible connecting peptide. HPVP-02 responsively disassembles in the acidic microenvironment of the tumor, efficiently penetrates the cell membrane, degrades E6 / E7 protein through the ubiquitin-proteasome pathway, restores the function of the host tumor suppressor protein p53 / pRb, and simultaneously blocks the PD-1 / PD-L1 pathway to activate the anti-tumor immune response. The fusion polypeptide of the present invention has the advantages of targeting precision, low toxicity and synergistic treatment, providing an innovative treatment strategy for HPV-related tumors.

The invention discloses a novel AR degradation agent as well as a preparation method and application thereof. The AR degradation agent is PROTAC with GROs (such as AS1411) as an MDM2 recruitment element, target protein AR and E3 ubiquitin ligase MDM2 can be drawn close in vivo, the AR is labeled with ubiquitin, and then the AR is degraded through a ubiquitin-proteasome pathway. Experiments show that the AR degradation agent can effectively degrade AR and generate corresponding curative effects (such as inhibition of tumor cell proliferation and promotion of tumor cell apoptosis), and has very good application prospects and research values.

The application discloses a stapling peptide targeting TRIB3 / SSRP1 interaction and application of the stapling peptide in preparation of anti-multiple myeloma drugs. Through a series of experiments such as immunoprecipitation coupling mass spectrometry, it is found that TRIB3 directly interacts with SSRP1 protein in multiple myeloma cells, thereby playing a role in promoting malignant proliferation of multiple myeloma, and TRIB3 promotes degradation of the SSRP1 protein through a ubiquitin-proteasome pathway. The stapling peptide 7695-SP5 inhibits malignant proliferation of multiple myeloma by specifically inhibiting TRIB3 / SSRP1 protein interaction. The stapling peptide 7695-SP5 can be used as a TRIB3 / SSRP1 protein interaction inhibitor to treat diseases caused by increased expression of TRIB3 and SSRP1 proteins, such as multiple myeloma, and is expected to be developed into a novel anti-tumor drug.

The present invention provides PIKfyve proteolytic agents and their uses. Specifically, the present invention provides compounds having the structure represented by formula (I), or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or prodrug molecules thereof. Because the compounds can target and degrade the PIKfyve protein via the ubiquitin-proteasome pathway, they can be used to treat indications mediated by the abnormal expression of the PIKfyve protein. JPEG2026514100000234.jpg51164

The application discloses a degradation agent based on inhibitor fusion covalent fragments and application, and belongs to the technical field of medicines. Specifically, the degradation agent is obtained by fusing covalent fragments of an inhibitor (+) JQ-1 of BRD4 protein. The degradation agent can target BRD4 protein and degrade BRD4 protein. The degradation activity of the degradation agent is screened through two experiments of high-content screening technology and Western blotting, and the best compound M4 in degradation activity is obtained. The compound M4 can induce significant degradation of BRD4 protein within 6 hours, and presents dose dependence; the mechanism of action is to degrade BRD4 protein through an ubiquitin-proteasome pathway mediated by E3 ubiquitin ligase DCAF11. Cell experiments prove that the compound M4 has a broad-spectrum anticancer ability.

The application discloses a morpholinyl triazine compound, a protein-targeted degradation agent based on a hydrophobic label, and a preparation method and application thereof. The application is based on the innovation of a source molecular skeleton, provides a hydrophobic skeleton based on the standardization, modularization, easy synthesis and derivatization of s-triazine, and adds a morpholinyl group in the design process to construct a novel hydrophobic label unit (M-Hyt), so that the hydrophobic label is directly endowed with inherent lysosome targeting tendency, realizes the dual-module degradation capability of the proteasome pathway and the lysosome pathway, and expands the range of degradable target proteins.

The invention relates to application of JND7064 as AXL molecular glue to preparation of drugs for preventing or treating tumors related to AXL high expression, in particular to application of JND7064 to treatment of triple negative breast cancer. The JND7064 induces degradation of AXL through a CRBN dependent ubiquitin-proteasome pathway, and the JND7064 is combined with an AXL non-kinase structural domain. In addition, the JND7064 selectively inhibits the proliferation of the MDA-MB-231 cells, and the JND7064 induces the MDA-MB-231 to generate G0 / G1 phase retardation and induces the cells to generate apoptosis.

The application provides application and method of stress protein USP1 (universal stress protein 1) in tomato bacterial disease, and the application finds that SlUSP1 is expressed in each tissue and is induced by pathogenic bacteria Pst DC3000 significantly. The SlUSP1 knockout and overexpression plants are constructed, and it is proved that the disease resistance is positively regulated: the disease spot of the knockout plant increases, the defense gene expression and the antioxidant enzyme activity decrease, and the resistance is enhanced. The interaction protein screening and verification show that SlUSP1 interacts with E3 ubiquitin ligase components SlWD1 / SlWD3 and exists in the form of a dimer, and the protein stability is regulated by 26S ubiquitin-proteasome pathway. SlUSP1 overexpression promotes stem thickening, branch increase and plant height reduction, and improves the expression of growth and development related genes, and the application plays a role in anti-lodging and growth regulation, and provides a key molecular target for disease resistance and high yield breeding.

The invention provides a micromolecular bifunctional chimera compound specifically binding to tau protein aggregate, the compound has a structure as shown in formula (I): A-linker-B (I), A is a depolymerization group specifically binding to pathological tau protein aggregate and promoting depolymerization of the tau protein aggregate, and B is a difunctional chimera group specifically binding to the tau protein aggregate and promoting depolymerization of the tau protein aggregate. B is a clearing group which is used for recruiting p62, LC3B or ubiquitin linker assemblies MDM2, cIAP, VHL and CRBN required by formation of cell autophagosome so as to promote tau protein aggregate to be cleared through cell autophagy or through a ubiquitin-proteasome pathway, and the linker is a linking group for connecting the group A and the group B. The compound can inhibit formation of tau protein aggregates and promote removal of pathological tau protein aggregates at the same time, and can be applied to prevention and treatment of AD, FTD and other diseases with abnormal aggregation of tau proteins.

This invention discloses a peroxisome-targeting chimeric compound, PexTAC, and its applications, belonging to the field of target protein degradation technology. The invention provides a peroxisome-targeting chimeric compound, PexTAC, with the general structural formula A-L-B, where A is the peroxisome-targeting module, L is the linker, and B is the target protein recognition module. PexTAC recruits target proteins to the peroxisome membrane and utilizes the endogenous E3 ubiquitin ligase SYVN1 for specific degradation via the proteasome pathway. This platform can not only target ROR1 to inhibit tumor growth but also induce ferroptosis through the bispecific PexTAC synergistic degradation of HSPA5 and GPX4. This invention overcomes the dependence of traditional PROTAC technology on limited E3 ligases, providing a novel modular degradation strategy for targeting "undruggable" proteins and organelle-related proteins.

The invention relates to the technical field of medicines, in particular to a compound for targeted degradation of mIDH1 protein and application of the compound. According to the invention, a series of compounds with a 'PL-Linker-EL' ternary structure are creatively designed and synthesized, so that a fundamental treatment strategy breakthrough from traditional'protein function inhibition 'to direct'pathogenic protein removal' is realized. The compound can be combined with mutant IDH1 (mIDH1) protein and E3 ubiquitin ligase in a targeted manner at the same time, and then mIDH1 is induced to be subjected to ubiquitination modification and is thoroughly degraded through a proteasome way, so that the problem of drug resistance caused by mutation is expected to be overcome, and a new treatment choice is provided for patients who are invalid or relapse in the existing therapy.