120 results about "Lysosomal targeting" patented technology

The invention discloses a lysosome targeted chimera based on Sortilin and application thereof. The lysosome targeted chimera comprises a ligand molecule of a lysosome targeted receptor and a ligand molecule of a targeted protein to be degraded, wherein the ligand molecule and the ligand molecule are connected through a linker; the lysosome targeting receptor is Sortilin, and the ligand molecule of the lysosome targeting receptor is a polypeptide targeting the Sortilin; the protein to be degraded is membrane protein or extracellular protein. Furthermore, the polypeptide of the targeted Sortilin is connected with an enzyme response sequence and an integrin receptor targeting sequence. According to the invention, the Sortilin-combined ligand neurotensin is functionally coupled with the neutralizing antibody or polypeptide of overexpression protein in targeted tumor or inflammatory diseases, and the Sortilin-combined ligand neurotensin has obvious treatment gain in malignant solid tumor and psoriasis models. The discovery promotes the transformation potential of the lysosome participating in the biological agent, and provides a dual strategy for realizing accurate degradation through receptor recruitment and microenvironment induction.

The invention discloses a covalent lysosome targeting chimera based on a nucleic acid aptamer and application of the covalent lysosome targeting chimera in protein degradation and immunotherapy, and belongs to the technical field of biology. The invention designs a covalent lysosome targeting chimera with click chemical reaction activity, and the simple and efficient covalent lysosome targeting chimera is used for realizing efficient protein degradation at the levels of cells and living bodies. When the tool is used for targeted degradation of immunotherapy biomarkers, immunogenic apoptosis of tumor cells can be caused, so that killing of an immune system to tumors is more efficiently activated. Meanwhile, the covalent lysosome targeting chimera overcomes the problem of immune-related side effects confronted by existing antibodies and polysaccharide peptide drugs, and can effectively avoid the potential occurrence risk of the immune-related side effects while efficiently degrading the target protein.

The present disclosure provides lysosomal targeting bifunctional molecules that target disease causing anti-MuSK autoantibodies for degradation. The lysosomal targeting bifunctional molecules include a ligand moiety that specifically binds to an asialoglycoprotein receptor (ASGPR), and which is linked via a carrier protein to a muscle-specific kinase (MuSK) polypeptide that specifically binds target anti-MuSK autoantibodies.

Disclosed are a recombinant fusion antibody, and an antibody-drug conjugate and use thereof. The recombinant fusion antibody includes an antibody, at least one lysosome-targeting peptide, and at least one linker peptide, wherein the antibody is fused with the lysosome-targeting peptide to form the recombinant fusion antibody via the linker peptide; wherein the lysosome-targeting peptide is at least one selected from the group consisting of a lysosome-sorting signal peptide from a Golgi-localized, γ-adaptin ear-containing, ARF-binding protein (GGA), a lysosome-sorting signal peptide from a mannose 6-phosphate receptor (MPR), a lysosome-sorting signal peptide from a lysosome-associated membrane protein (LAMP), and a variant; wherein the variant is a peptide with one or more amino acids substituted, deleted, and / or added when aligned with the lysosome-sorting signal peptide from a GGA, a MPR or a LAMP. Compared with the original antibody, the internalization and lysosomal trafficking ability of the recombinant fusion antibody are significantly improved.

The invention relates to a coumarin-based fluorescent probe as well as a preparation method and application thereof in the aspect of HClO detection, and belongs to the technical field of HClO detection. The invention discloses a coumarin-based fluorescent probe W (O-(3-((2-morpholinyl ethyl) carbamoyl)-2-oxo-2hydrogen-benzopyran-7-yl) dimethyl thiocarbamate) prepared on the basis of an intramolecular charge transfer (ICT) mechanism, and a preparation method of the coumarin-based fluorescent probe W. The novel lysosome targeting fluorescent probe contains coumarin as a fluorophore, a morpholine group as a targeting group and a dimethyl thiocarbamate group as a recognition group, is a novel lysosome targeting fluorescent probe, and has excellent performances of high selectivity, low detection limit, low cytotoxicity, high resolution and the like in the aspect of HClO detection; the method can be used for detecting the content of endogenous and exogenous hypochlorous acid in living cells.

The present disclosure provides lysosomal targeting bifunctional molecules that target disease causing anti-TSHR autoantibodies for degradation. The lysosomal targeting bifunctional molecules include a ligand moiety that specifically binds to an asialoglycoprotein receptor (ASGPR), and which is linked via a carrier protein to a thyroid stimulating hormone receptor (TSHR) polypeptide that specifically binds target anti-TSHR autoantibodies.

Provided herein is disclosure of a recombinant bifunctional protein or polypeptide capable of binding to a cell surface receptor for lysosome targeting that is made up of an N-glycosylated peptide comprising at least one N-glycan group and a protein of interest, or antibody or antibody fragment capable of binding to a protein of interest. Also provided herein are methods for producing said recombinant bifunctional protein. Also provided herein are methods for lysosomal degradation of a protein of interest comprising introducing to a cell the peptide sequence of the recombinant bifunctional protein.

The invention provides an engineered exosome for treating sepsis as well as a construction method and application of the engineered exosome, and belongs to the technical field of biological medicines. The invention provides an engineered exosome for treating sepsis. The engineered exosome comprises the following fusion proteins: a first fusion protein formed by a cryptochrome 2 protein and an exosome scaffold protein, a lysosome targeting peptide, and a second fusion protein formed by a Caspase 1 protein recruitment protein structural domain and a cryptochrome 2 protein ligand. The cell level and animal level prove that the engineered exosome can efficiently and accurately inhibit secretion of inflammatory factors, reduce inflammatory response and pathological conditions in a sepsis animal model, and restore animal functions of the sepsis model to a certain extent. Therefore, the engineered exosome provided by the invention provides a new means for treating sepsis, and has great market popularization and application values.

The invention discloses a multivalent lysosome targeting chimera and application thereof in protein degradation and immunotherapy, and belongs to the technical field of immunotherapy. The multivalent lysosome targeting chimera provided by the invention can efficiently recognize and combine a target protein and a lysosome shuttle receptor to cause degradation of the target protein through a lysosome way. The lysosome targeting chimera can continuously act at a target part, achieves the beneficial effects of low dosage and high curative effect, can effectively block a PDL1 / PD1 signal axis, causes tumor cell immunogenic death, induces strong anti-tumor immune response, and has multiple effects of inducing tumor apoptosis and blocking immune checkpoints.

The invention discloses a small molecule compound, a water-soluble fluorescent probe as well as a preparation method and application of the water-soluble fluorescent probe, and belongs to the technical field of medicines. According to the invention, a small molecule compound NQL containing a naphthalimide fluorophore is synthesized, and then a water-soluble fluorescent probe CS-NQL is prepared by forming Schiff base and coupling the Schiff base with chitosan oligosaccharide. The CS-NQL has environmental viscosity responsiveness and lysosome targeting specificity, so that tumor and inflammatory cell imaging can be carried out in a visible light range. The CS-NQL and DNA are subjected to electrostatic self-assembly to form nanoparticles CS-NQL coated DNA NPs, and the nanoparticles CS-NQL coated DNA NPs can generate active oxygen under an anoxic condition; under the irradiation of 660 nm laser, HeLa cell apoptosis can be induced, and an antibacterial effect is shown. An in-vivo experiment shows that CS-NQL-coated DNA NPs shows a strong anti-tumor immune response under the irradiation of 660 nm laser, so that the tumor is completely eradicated.

The application discloses a LYTAG-Gem compound for enhancing the anti-tumor effect of gemcitabine and application thereof, relates to the technical field of biological medicine, and particularly relates to a gemcitabine (Gem) targeted delivery system based on a lysosome targeting chimera (LYTAC) and application thereof in enhancing the anti-tumor process. 2+ The system is assembled from heavy chain ferritin, Ni 2+ , NTA-PEG5000-DBCO and a targeting ligand TPP-1-N3 in a specific mass percentage, can efficiently load Gem and form a nano compound with a particle size of about 59-79 nm, the system targets tumor cells through heavy chain ferritin, and realizes site-specific release of Gem in cells by means of an endocytosis-lysosome pathway mediated by the LYTAC structure, in-vivo pharmacodynamic experiments show that the LYTAC-Gem compound can significantly inhibit the tumor growth of a KPC pancreatic cancer mouse model, molecular mechanism research further reveals that the LYTAC-Gem compound can down-regulate the expression of PD-L1 protein in tumor tissues, and it is indicated that the LYTAC-Gem compound has the potential to activate an anti-tumor immune response, and the application provides a novel targeted delivery strategy for overcoming the toxic side effects and tumor drug resistance of gemcitabine.

The invention provides a novel lysosomal targeting fusion protein based on fusion of an IGF2 mutant and an antibody, and a method for degrading a protein by using the novel protein construct.

The invention discloses a lysosome targeted degradation system based on a DNA phase separation aggregate as well as a preparation method and application of the lysosome targeted degradation system, and belongs to the technical field of biological medicine and nanotechnology. The lysosome targeted degradation system based on the DNA phase separation aggregate comprises an RNA-DNA tetrahedral framework with a cohesive end, the RNA-DNA tetrahedral framework is formed by self-assembly of a core chain and an edge chain through complementary base pairing, the edge chain is a DNA-RNA chimeric oligonucleotide chain, and the DNA-RNA chimeric oligonucleotide chain is a DNA-RNA chimeric oligonucleotide chain. One or more sections of RNA ribonucleotide sequences which can be specifically recognized and cut by RNase H enzyme are embedded in the sequence, and the tail end of the RNA ribonucleotide sequence is modified with a cohesive tail end for driving phase separation and a cell membrane anchoring group; the RNA-DNA tetrahedral framework is modified with an aptamer of a targeted membrane protein. After entering cells, the system is subjected to liquid-liquid phase separation in a lysosome acid environment through interaction of cohesive ends, a micron-sized large-size aggregate is formed in situ, the residence time of a nano-drug in the lysosome is prolonged, and efficient degradation of target membrane protein is realized.

This invention discloses a naphthimide-based fluorescent probe for detecting HClO and its preparation method. The fluorescent molecular probe uses naphthimide as the fluorophore and C=N as the specific reaction site for HClO. Due to the presence of the naphthimide fluorophore, the probe molecule exhibits two-photon properties, enabling deep tissue penetration, reducing background noise, and facilitating fluorescence imaging of biological systems. Furthermore, the introduced morpholine group allows for lysosomal targeting, enabling the monitoring of hypochlorous acid concentration levels in lysosomes, making it a valuable tool for early disease diagnosis. In addition, this type of probe molecule is simple to synthesize, operates under mild reaction conditions, exhibits stable optical properties, and has a high synthesis yield. It can detect a wide range of HClO, making it practically valuable in fields such as biochemistry and environmental science.

The present invention provides a dual-cell-targeted luminescent near-infrared fluorescent probe (E)-4-(4-(bis(4-(2-morpholinoethoxy)phenyl)amino)styryl)-1-(2-hydroxyethyl)quinolin-1-ammonium hexafluorophosphate (V), namely the fluorescent probe MoTQu. This dual-cell-targeted fluorescent probe contains a quinolinium cation moiety and targets mitochondria through electrostatic interaction with the electronegative mitochondrial membrane; the introduction of a weakly basic morpholine ring in the triphenylamine tail chain of this fluorescent probe targets lysosomes. At the same time, the preparation method and application of this probe are disclosed. The fluorescent probe of the present invention can not only light up different organelles in response to time, but also effectively improve the killing efficiency of cancer cells through the synergy of mitochondrial- and lysosome-targeted photodynamic therapy, and thus has a powerful effect on the ablation of photodynamic cancer cells.

The invention relates to the technical field of biological medicine, in particular to application of hordenine in preparation of a lysosome targeting preparation. The hordenine can be captured by the lysosome and accumulated in the lysosome, so that the hordenine has the characteristic of targeting the lysosome, and the hordenine can be used for preparing the lysosome targeting preparation. Hordenine is small in toxic and side effects and high in safety, and the problems that existing lysosomal targeted compounds such as chloroquine are high in toxicity and narrow in therapeutic window are effectively solved.

The invention provides a polyporus polysaccharide microneedle composition with a CD47 protein degradation function. The polyporus polysaccharide microneedle composition comprises a lysosome targeting chimera for degrading CD47 protein, polyporus polysaccharide and hyaluronic acid. The invention also provides a preparation method of the lysosome targeting chimera for degrading the CD47 protein. The invention also provides a microneedle prepared from the polyporus polysaccharide microneedle composition. The invention also provides a preparation method of the polyporus polysaccharide microneedle with the CD47 protein degradation function and application of the polyporus polysaccharide microneedle in preparation of medicines for treating tumors. According to the microneedle, on one hand, CD47 protein in melanoma tumor tissue can be efficiently degraded, then the phagocytosis effect of macrophages on tumor cells is enhanced, on the other hand, polyporus polysaccharide in the microneedle can promote the macrophages to be polarized towards anti-tumor types, and the anti-tumor activity of the macrophages is further enhanced. The immunosuppressive microenvironment is remodeled while CD47 is degraded, and the efficient and synergistic anti-tumor effect of the two drugs is achieved.

Provided herein are bifunctional lysosomal targeting degraders that comprise folate or a folate analog configured to bind to folate receptor as a shuttle molecule for lysosome degradation, and a protein binder configured to bind a membrane or extracellular protein of interest. The bifunctional degraders find use, e.g., for selectively targeted degradation of membrane and extracellular proteins via the endosomal / lysosomal pathway. Also provided herein are compositions comprising the bifunctional degraders, as well as methods of using the bifunctional degraders.

The application discloses application of a lipoic acid analogue in preparation of a product for relieving myocardial cell hypertrophy, and the lipoic acid analogue DMAE-LA is N -(2-(dimethylamino)ethyl)-5-(1,2-dithiopentyl-3-yl)valeric amide. DMAE-LA can effectively reduce ISO-induced myocardial hypertrophy of mice, reduce heart weight index and ANP and BNP expression, and significantly improve heart function. A small dose (2-10 μM) of a lysosome-targeting lipoic acid analogue DMAE-LA can effectively improve Ang II-induced myocardial hypertrophy and oxidative stress in H9c2 cells, and the protective effect is better than that of a high dose (200-400 μM) of LA. As a new substitute of traditional LA, DMAE-LA shows great potential for prevention and treatment of cardiovascular diseases.

The present invention belongs to the field of medicinal chemistry technology and relates to a lysosomal-targeted nitroreductase-responsive fluorescent probe based on a triphenylamine backbone, its synthesis method, and its application. The triphenylamine derivative-based lysosomal-targeted nitroreductase-responsive fluorescent probe provided by the present invention does not emit light upon initial entry into cells. However, after a period of culture in cancer cells, the electron-withdrawing nitro group is reduced by the intracellular nitroreductase. Under laser irradiation, the charge within the fluorophore shifts, resulting in fluorescence. The present invention also provides a method for synthesizing the lysosomal-targeted nitroreductase-responsive fluorescent probe and its use in bioimaging.

The invention provides a specific protein degradation system and application. A specific protein degradation system is introduced in the lentivirus production process, membrane proteins such as CAR on the surfaces of production cells are degraded, carrier surface membrane protein modification is reduced, and therefore the off-target risk is reduced, and the transduction efficiency is improved. The specific protein degradation system comprises a monovalent degradation agent, a disturbance type degradation agent, molecular glue and a difunctional degradation agent; the difunctional degradation agent comprises one or more of a lysosome targeting chimera, a proteolysis targeting chimera and an autophagy targeting chimera.

To provide a means capable of inducing decomposition of a new protein which can be comprehensively and generally used for all cells.SOLUTION: A peptide compound comprising a target-binding moiety, a cell membrane-penetrating peptide moiety, and a lysosome-inducing peptide moiety.SELECTED DRAWING: None

The present invention belongs to the field of chemical analysis and detection technology, and provides a pyrazoline derivative lysosome-targeted biological thiol fluorescent probe and its preparation method and application. The preparation method of the pyrazoline derivative lysosome-targeted biological thiol fluorescent probe of the present invention comprises the following steps: mixing compound 1, 2-chloro-3,5-dinitropyridine, a base and an organic solvent and reacting to obtain a pyrazoline derivative lysosome-targeted biological thiol fluorescent probe. The fluorescent probe of the present invention can monitor the concentration fluctuations of Cys, Hcy and GSH in living cell lysosomes in real time by fluorescence imaging, and has the advantages of high selectivity, high sensitivity and rapid response; good selectivity and low cytotoxicity make it an ideal tool for simultaneous detection of Cys, Hcy and GSH.

This invention relates to a lysosome-targeting fluorescent dye based on the BODIPY structure and its synthesis method, belonging to the field of organic fluorescent dyes. The invention designs and synthesizes the lysosome-targeting fluorescent dye BDP. The dye molecule uses BODIPY as the parent structure, and a novel lysosome-targeting fluorescent dye molecule is synthesized by introducing diphenylphosphine salt and tert-butyloxycarbonyl groups. The synthetic route of this dye is simple, it possesses excellent photostability, and exhibits good resistance to interference from ions, amino acids, and viscosity. Furthermore, this dye demonstrates superior fluorescence performance in a variety of common solvents, with fluorescence quantum yields exceeding 0.70. Experimental results show that this fluorescent dye can precisely target lysosomes in living cells, demonstrating promising applications in the field of bioimaging.

The invention relates to compounds and methods that include a lysosomal-targeting antibody linked to a lysosomal enzyme inhibitor for the treatment or prevention of conditions or disorders, such as cancer.

The application discloses a kind of strong electron donor triphenylamine modified coumarin dyes, its synthesis method and application;The dye has blue-green light excitation characteristics, the maximum absorption wavelength is 415-425 nm, the maximum emission wavelength is 495-505 nm, and excellent lysosome targeting and positioning ability is shown.It overcomes the problem of low efficiency of traditional coumarin as photosensitizer in molecular structure design, realizes the efficient I type photodynamic effect, can generate active oxygen under light efficiently.In addition, this dye has good cell membrane permeability and low dark toxicity, suitable for biomedical imaging, photodynamic therapy of tumor and other fields.The synthesis method is simple, raw materials are easy to obtain, and the yield is high, suitable for large-scale production.Experiments show that the dye can effectively enrich in cell lysosomes, realize precise killing of cancer cells, and show great potential in cancer diagnosis and treatment integration.

Provided herein are antigen-binding proteins (ABPs) that selectively bind to M6PR and its isoforms and homologs, and compositions comprising the ABPs. Also provided herein are bispecific antigen-binding proteins (ABPs) that selectively bind to internalizing receptors, and a soluble target molecule or cell surface target molecule and its isoforms and homologs, and compositions comprising the ABPs.

The present invention relates to the field of biomedicine technology, and specifically to a lysosome-targeted chimera for targeted degradation of endothelial vascular growth factor, and a preparation method and application thereof. The lysosome-targeted chimera includes an aptamer targeting the endothelial vascular growth factor to be degraded and an aptamer of a lysosome-targeted receptor, wherein the aptamer targeting the endothelial vascular growth factor to be degraded can target and bind to the endothelial vascular growth factor, and the aptamer of the lysosome-targeted receptor can transport the bound endothelial vascular growth factor into the lysosome for specific degradation. The lysosome-targeted chimera for targeted degradation of endothelial vascular growth factor provided by the present invention provides a new idea for the treatment of neovascular eye diseases.

The invention belongs to the technical field of biomedical detection, and relates to a quinoxaline-derived Aza-BODIPY AIE fluorescent probe, the probe is composed of three parts of fluorophore Aza-BODIPY, rotor benzothiazole and lysosome targeted morpholine, the Aza-BODIPY and benzothiazole are connected through a-C = N-C-group, and the probe is a quinoxaline-derived Aza-BODIPY-AIE fluorescent probe. A precursor intermediate probe 1 is formed by connecting a fluorophore Aza-BODIPY and a rotor benzothiazole through a-C-C = N-group. The invention further discloses a synthesis method of the fluorescent probe and application of the fluorescent probe to lysosome viscosity detection. The probe system disclosed by the invention has significantly increased Stokes shift, and effectively avoids overlapping of excitation / emission spectrums; the fluorescent probe shows typical aggregation-induced emission (AIE) characteristics, and fluorescence enhancement is most remarkable under the condition that the water content is 40-50%; the fluorescent probe has wide-range viscosity response capability (2-610cP), 24 times of fluorescence enhancement can be generated at most, and the detection limit is as low as 0.27 cP; the lysosome co-localization performance is excellent, and the cell compatibility is good; the high-contrast real-time imaging monitoring on the viscosity of the living cell lysosome can be realized.

The present disclosure describes lysosome-targeting chimeras having at least one target-binding moiety capable of specifically binding a cell surface molecule or an extracellular molecule; and at least one thiol-responsive moiety. Methods of making and using the lysosome-targeting chimeras are also provided.