95 results about "Cathepsin" patented technology

The invention discloses a cathepsin B activated fluorescent probe which comprises a dicyanoisosulfone fluorescent report unit and a cathepsin B specific restriction enzyme cutting site GFLG peptide chain. When CTSB specifically cuts a GFLG peptide chain, a DCO molecule with an amino group with relatively strong electron donating ability is generated, so that the fluorescence emission behavior of the probe is rapidly activated through a one-step enzyme catalysis reaction. The invention also provides a preparation method of the cathepsin B activated fluorescent probe. The invention also provides a nano particle for packaging the cathepsin B activated fluorescent probe, and the nano particle is simple in preparation process and mild in reaction condition. The cathepsin B activated fluorescent probe is prepared into nanoparticles, and the nanoparticles can realize accumulation of the material in tumor tissues and accurate imaging in apoptotic tumor cells by enhancing the permeation retention effect, have better biocompatibility and can be used for detecting the apoptotic tumor cells.

The invention relates to the technical field of biological medicine, in particular to a polypeptide self-assembly PROTAC degradation agent and a preparation method and application thereof. The polypeptide self-assembly PROTAC degradation agent comprises a self-assembly group, an E3 ligase recognition group, a cathepsin response group, an FOXM1 targeting binding group, a connecting peptide and an integrin alpha 6 targeting peptide, the amino acid sequence of the FOXM1 targeted binding group is as shown in SEQ ID NO: 1. According to the polypeptide-based nano delivery system, the drug delivery efficiency is remarkably improved, meanwhile, the risk of side effects is reduced to the minimum through controllable release of active fragments, and a basis is provided for preparation of tumor drugs.

The present invention is directed to cathepsin inhibitor conjugates, precursors and compositions comprising thereof. Further, methods of use such as for the treatment and prevention of a disorder associated with abnormal cathepsin activity in a subject in need thereof are also provided.

The invention discloses a polypeptide, a polypeptide / siRNA compound and application thereof, and belongs to the field of biological medicine preparations. The amino acid sequence of the polypeptide disclosed by the invention is as follows: Nap-FFKYGFRRGHHHHRHHHR or Nap-FFKYGFRRGHHHHKHHK. A polypeptide / siRNA compound formed by the polypeptide and siRNA is uniform in particle size and good in stability, the hydrophobic end of the polypeptide / siRNA compound can respond to cathepsin B in lysosome to be assembled into nanofibers, a membrane of the lysosome is damaged, and then escape of the lysosome of the siRNA is promoted; after the siRNA / cationic peptide part is released into cytoplasm, the cationic peptide responds to the change of cytoplasm pH to reduce the electropositivity of the siRNA molecule, so that efficient cytoplasm delivery of the siRNA molecule is realized, and the siRNA molecule is promoted to play a silencing effect. The embodiment of the invention shows that the Pep / siRNA compound disclosed by the invention has relatively strong in-tumor retention capacity in a mouse body and can effectively inhibit the growth of breast cancer tumors.

The invention discloses an electrochemical urine biopsy system for cathepsin B analysis and a detection method of the electrochemical urine biopsy system. The electrochemical urine biopsy system comprises gold nanoparticles AuNPs, a peptide-peptide nucleic acid PNA series probe and an electrochemical sensor. The peptide-peptide nucleic acid tandem probe is combined with gold nanoparticles through a mercaptan modified sequence to form a spherical nanostructure with the diameter of 15 nm, a polypeptide substrate sequence serves as a specific reaction substrate of cathepsin B, and PNA provides stability and a signal shielding function. The electrochemical sensor is based on a cutting enzyme-assisted DNAwalker mechanism, signal amplification is started through methylene blue MB release, and high-sensitivity detection of the released PNA probe is achieved. The system provided by the invention has the characteristics of high specificity, high sensitivity and rapid response, can realize quantitative analysis of cathepsin B through noninvasive urine biopsy, and provides a new technical means for early diagnosis and treatment monitoring of tumors.

The invention belongs to the field of biological medicine, and relates to a human serum albumin covalent binding type targeted folate receptor micromolecule drug conjugate prodrug and application thereof. The prodrug disclosed by the invention has a structure as shown in a formula I, six-carbon maleimide is used as a site combined with endogenous albumin, and albumin is used as a carrier to deliver the drug. The prodrug can increase accumulation of the drug in tumors under the EPR effect. A dipeptide chain composed of valine and alanine is used as a cleavage site of cathepsin B, an adapter composed of p-aminobenzyl ether and N-methylamino-4-nitrophenol releases drugs in an acidic environment, an azidohexanoic acid structure is added to a side chain of p-aminobenzyl ether, so that the site of a targeting ligand can be increased, and SN38 is used as a small molecule cytotoxic load. The micromolecular prodrug has dual functions of active targeting and passive targeting, and can effectively improve the concentration in solid tumors, reduce toxic and side effects and improve the anti-tumor effect under the mediation of related receptors.

Peptide compounds derived from cathepsin G (CG), neutrophil elastase (NE), and cationic antimicrobial protein of 37 kDa (CAP37), and methods of their use in inhibiting and / or reversing polymerization of amyloid β peptide into oligomers and / or fibrils, and / or disaggregating amyloid β plaques, and methods of use of the peptide compounds in treatments of, for example, Alzheimer's disease, cerebral amyloid angiopathy, dementia, and / or neuroinflammation, and / or symptoms thereof are disclosed.

The invention discloses cell-penetrating peptide modified enzyme-sensitive PDC type PROTAC as well as a preparation method and application thereof, and belongs to the technical field of tumor targeted therapy. The cell-penetrating peptide modified enzyme-sensitive PDC type PROTAC is obtained by modifying a target protein ligand with a cell-penetrating peptide and an enzyme-sensitive Linker (GFLG) as an antitumor drug, has the capability of releasing the PDC type PROTAC under the catalysis of cathepsin B, has small influence on the cell activity of U251 cells, U87 cells and HEK293 cells, has proliferation inhibition activity on the U251 cells and the U87 cells, and can be used for preparing an antitumor drug. The polypeptide can degrade target proteins in U251 cells and U87 cells, can induce apoptosis of the U251 cells and the U87 cells, has an influence on the cycle of the U251 cells, can be used for preparing antitumor drugs (in the aspects of targeted protein degradation and membrane permeation), has a good application prospect in preparation of drugs targeting human brain glioma cells, and can be used in another important field of PROTAC drug development.

The invention relates to a radioactive metal labeled antibody obtained by labeling an antibody with a radioactive metal. A functional chelate linker is coupled to the antibody, and the functional chelate linker is provided with: a chelate part capable of coordinating with a radioactive metal ion; and a functional unit having a function of improving intracellular retention. It is preferable that the functional unit has a structure obtained by polymerizing ethyleneimine or ethylene glycol, or a structure capable of binding to cathepsin B. The functional unit preferably has a structure obtained by polymerizing ethyleneimine at a degree of polymerization of 1-7 (inclusive).

The invention provides an activatable semiconductor polymer as well as a preparation method and application thereof. The activatable semiconductor polymer disclosed by the invention can be efficiently accumulated at a tumor site, due to the existence of a side chain electron withdrawing group, the fluorescence of the polymer is in a quenched state, the fluorescence of the polymer is recovered after tumor markers such as biological mercaptans, active oxygen and cathepsin B are respectively responded, and accurate imaging and sonodynamic therapy can be carried out at the tumor site. Meanwhile, the activatable semiconductor polymer can mark immune cells (such as dendritic cells and macrophages) and track the process of transferring the immune cells from tumors to tumor drainage lymph nodes.

The invention discloses a glucan-based MMAE conjugate as well as a preparation method and application thereof, and relates to the technical field of medicines. The conjugate takes glucan with good biocompatibility as a carrier, and is covalently connected with a cytotoxic drug MMAE through a VC peptide linker capable of being cut by cathepsin B. The conjugate has good serum stability, can specifically release drugs at a tumor site, and realizes efficient tumor uptake by virtue of the stealth effect of glucan and potential GLUT1 targeting. In-vitro and animal experiments show that the conjugate has a remarkable treatment effect on pancreatic cancer and is low in systemic toxicity.

This invention discloses an enzyme- and pH-responsive nucleic acid loading and delivery material and its preparation method. The material can be used for efficient loading and delivery of nucleic acid molecules. The preparation method uses amphiphilic zwitterionic monomers to improve the reverse emulsion polymerization system, enhancing polymerization at the two-phase interface and avoiding the extrusion effect of polymerization in the aqueous core on nucleic acid molecules, thereby improving the loading efficiency of nucleic acid molecules. Further preparation of cross-linking agents MP-CL and CB-CL, which can cleave in response to matrix metalloproteinase II or cathepsin B, endows the nanogel with the ability to respond to charge reversal in the tumor matrix and to release nucleic acid molecules from tumor cells. The acid-sensitive blocks on the amphiphilic monomers give the nanogel lysosomal escape capability. The delivery material can efficiently deliver nucleic acid molecules into cells and exhibits excellent stability and biosafety.

The invention discloses an albumin coupling medicine as well as a preparation method and application thereof. The cathepsin B response type camptothecin albumin coupling drug is innovatively designed and synthesized by taking albumin as a carrier, the albumin coupling drug has good cathepsin B response drug release capability, efficient tumor targeted delivery of the drug is realized, camptothecin is responded and released in tumor cell lysosome, and the drug delivery efficiency is improved. The specific anti-tumor effect is achieved. The invention provides a regulation and control method in the aspects of preparation, drug loading capacity and in-vitro release of the albumin coupled drug, size effects in the aspects of cellular uptake, cytotoxicity, tumor targeting and retention are illustrated, and guidance is provided for designing an efficient and safe tumor drug delivery system.

The present invention relates to a method for preparing controlled-release enzyme-loaded microspheres for preventing and treating skin photoaging and their application, belonging to the field of pharmaceutical engineering drug preparations. The present invention's preparation method produces controlled-release enzyme-loaded microspheres loaded with cathepsin D and cathepsin K, combining the advantages of microsphere controlled release with the therapeutic strategy of cathepsins. The resulting microspheres have the effect of preventing and treating skin photoaging, representing a major breakthrough in the research and development of specific drugs for preventing and treating photoaging and related skin lesions. The present invention can provide a new strategy for developing better small-molecule drugs for the prevention and treatment of photoaging and related skin diseases, and has important theoretical and practical value.

Compositions and methods are provided of a therapeutic nanoparticle composed of collagenase IV linked via a linker (e.g. cathepsin B cleavable linker) to ferumoxytol (iron oxide). The collagenase IV is key in the composition intended for the breakdown of the tumor wall as the collagenase. Such compositions and methods are aimed at solving at the same time two of the main challenges of current approaches in the treatment of glioblastoma multiforme (GBM) which are low specificity and poor uptake.

This invention relates to compounds that are useful as inhibitors, in particular as inhibitors of Cathepsin K (CatK), and to a method of inhibiting cathepsin activity, comprising administering a compound or formulation comprising a compound according to the invention.

The inventors have prepared a novel anti-Cath-D antibody (F1M1) that can reduce tumor growth in a Cath-D secreting basal-like TNBC cell line with strong immune infiltration, without significant toxicity. The F1M1 antibody prevents recruitment of immunosuppressive M2 polarized tumor-associated macrophages (TAMs) and induces activation of natural killer cells in the tumor, and the F1M1 also enhances activation of antitumor M1 polarized TAM, recruitment and maturation of conventional cDC1 dendritic cells in the tumor to promote antigen presentation and reduce depletion marker expression of CD4 + and CD8 + T cells in the tumor and drainage lymph nodes. It is worthy of noting that the affinity of the antibody F1M1 to Cath-D is better than that of the antibody F1 prepared by the inventor in advance. The inventors also have prepared a novel Fc-optimized F1M1-Fc + human antibody which can promote ADCC induction of cancer cells and CAF, improve anti-tumor efficacy, and trigger recruitment, activation and cytotoxic activity of NK cells in tumors. The F1M1-Fc + F1M1-Fc + can inhibit the growth of MDA-MB-231 and SUM159 TNBC cell xenografts and two TNBC-PDX (one of the TNBC-PDX is resistant to neoadjuvant chemotherapy), and has no obvious toxicity. In addition, the F1M1-Fc < + > improves the treatment effect of the paclitaxel and enzalutamide combined medicine. Thus, the present invention relates to anti-cathepsin-D antibodies and their use in the treatment of cancer, in particular triple negative breast cancer.

The invention belongs to the field of biological medicine, and particularly relates to a nano-drug based on chondroitin sulfate as well as a preparation method and application of the nano-drug. Chondroitin sulfate (CS) and dasatinib (DAS) are connected through a GFLG connexon responded by cathepsin B (CTSB) to prepare the prodrug CS-GFLG-DAS (CGD), the prodrug CS-GFLG-DAS (CGD) is used for reversing the phenotype of cancer-related fibroblasts and reducing the biosynthesis of extracellular matrixes, fibrotic tumors are efficiently treated, and a new perspective is provided for optimizing the application of immunotherapy in fibrotic tumors.

The invention discloses a polypeptide coupling drug and a preparation method and application thereof, and belongs to the technical field of biological medicine, the polypeptide coupling drug is formed by bonding and connecting cyclic peptide molecules, connecting arms, spacers and antibiotic drugs through chemical bonds; aIP-III D4A amide and structural analogues of AIP-III D4A amide are selected as cyclic peptide molecules; the connecting arm selects a molecule which is sensitive to the specificity of cathepsin B in lysosome; and the spacer is a structural fragment capable of being automatically degraded. The polypeptide coupling drug has a good antibacterial effect, especially has an outstanding treatment effect on intracellular bacterial infection which is relatively difficult in current clinical treatment, and can be used for preparing efficient antibacterial drugs.

The invention relates to the field of biological medicine, in particular to an endoplasmic reticulum targeting peptide, an agonist, a preparation method and application. Wherein the agonist comprises an endoplasmic reticulum targeting peptide, and further comprises a mitochondrial membrane disturbing sequence and a sequence with cathepsin B response, the mitochondrial membrane disturbing sequence is KLAKLAK 2, and the sequence with cathepsin B response is GFLG; the endoplasmic reticulum targeting peptide comprises a KKKAA peptide sequence, and chlorin e6 and R8 peptide are connected to the KKKAA peptide sequence; the mitochondrial membrane disturbing sequence is connected to the R8 peptide through a sequence with cathepsin B response. According to the scheme, the characteristics of biochemical information interaction and tumor growth regulation of the mitochondria and the endoplasmic reticulum are utilized, excessive stress of the endoplasmic reticulum and a mitochondria calcium uptake channel are activated at the same time in a safe and controllable mode, free Ca < 2 + > in the endoplasmic reticulum rapidly flows into the mitochondria, the steady states of the endoplasmic reticulum and the mitochondria of tumor cells are damaged, and the tumor growth is controlled. And the two synergistically induce cells to start an apoptosis procedure, so that the aim of treating diseases is fulfilled.

The invention relates to a cathepsin B sensitive fatty acid-adriamycin prodrug as well as albumin nanoparticles, a preparation method and application thereof, and belongs to the technical field of medicines. The cathepsin B sensitive fatty acid-adriamycin prodrug is a prodrug as shown in a formula (I), a geometric isomer thereof, and pharmaceutically acceptable salts, hydrates and solvates thereof, wherein n is equal to 0-14. The invention also relates to a combined albumin nanoparticle prepared by entrapping the cathepsin B sensitive fatty acid-adriamycin prodrug by using human / bovine serum albumin as a carrier. The albumin nanoparticles are small in particle size and uniform in form, have good placement stability and colloidal stability, can stably exist in systemic circulation and normal tissues, and release a parent drug adriamycin after being taken by tumor cells and hydrolyzed by cathepsin B; therefore, specific killing of tumor cells is realized without generation of serious toxic and side effects, and good clinical development prospects are achieved.

Anti-VEGF proteins, including the VEGF trap protein aflibercept, can be manufactured to have a low content of an aspartyl protease (e.g., a low content of cathepsin D), for example, less than 1 ppm of the aspartyl protease.

In this vein, we present CTLAP, a fluorogenic probe that is rapidly activated by CTL and displays good selectivity over CTB and CTV, the closest competing analytes for CTL activity probes. CTLAP exhibits intrinsically low background fluorescence, which we attribute to the notably low quantum yield measured for the probe. CTLAP demonstrates markedly higher turn-on ratios (24-fold) and moderately improved enzyme selectivity (6- to 10-fold) when compared to Z-FR-AMC (10-fold turn-on ratio, 6- to 7-fold selectivity), a commercially available CTL-selective probe commonly used to detect CTL activity in mixed samples. Optimum selectivity for CTL is achieved within 10 min of incubation with the enzyme, suggesting that CTLAP is amenable for rapid detection of CTL, even in the presence of competing cathepsins.

The invention discloses an application of a cathepsin D inhibitor in preparation of a medicine for preventing or treating osteoarthritis, and an application of the cathepsin D inhibitor in preparation of a medicine for inhibiting degradation of type II collagen and / or articular cartilage. The invention relates to an application of a cathepsin D inhibitor in preparation of drugs for inhibiting expression of cathepsin D in bone joints. In the application, the cathepsin D can effectively relieve tissue lesions of osteoarthritis.

The present disclosure relates to a cancer-targeting peptide that can be cleaved by cathepsin B in cancer cells and is characterized by forming prodrug nanoparticles together with an anticancer agent, wherein the preparation of carrier-free prodrug nanoparticles may provide a new approach to cancer treatment and may significantly improve cancer targeting and the therapeutic efficacy of an anticancer agent.

The invention discloses application of a gene editing virus interfering expression and secretion of enzyme prototype cathepsin D in brain trauma, belongs to the field of gene functions and application, and finds that brain injury is aggravated and nerve dysfunction is aggravated due to the fact that the level of the enzyme prototype cathepsin D in plasma is increased due to the brain trauma through detection. The mechanism is as follows: the enzyme prototype cathepsin D enhances the transendocytosis effect of cerebral vascular endothelial cells after brain trauma, so that plasma inflammatory factors are gathered in damaged brain tissues; meanwhile, the expression of cerebrovascular endothelial cells VCAM-1 is also up-regulated, and neutrophil infiltration in an injured brain region after brain trauma is intensified. Research finds that down-regulation of plasma enzyme prototype cathepsin D can alleviate inflammatory factor concentration and neutrophil density in a brain injury area after trauma, and alleviate neurological function impairment of mice. Aiming at the functions of the plasma prototype cathepsin D, a strategy for reducing the plasma level of the plasma prototype cathepsin D by a gene editing technology for interfering the prototype cathepsin D is provided for treating the cerebral trauma.

The invention discloses a human leukemia cell targeted cell-penetrating peptide modified enzyme sensitive PDC type PROTAC as well as a preparation method and application thereof, and belongs to the technical field of tumor targeted therapy. The PDC type PROTAC is formed by connecting a hypoxia inducible factor 1 alpha (HIF-1alpha) protein fragment and imatinib through dodecanedioic acid, and is further modified through a human leukemia cell targeted cell-penetrating peptide Cyclo-C9C-R and a cathepsin B sensitive sequence GFLG. The modified PDC type PROTAC can release original drugs under the catalysis of cathepsin B, has small influence on THP1 cell activity, but can effectively inhibit proliferation of K562 cells and KU812 cells, degrade target proteins, induce cell apoptosis and influence cell cycles, so that the PDC type PROTAC has remarkable advantages in the aspect of preparation of antitumor drugs, and has broad application prospects. Particularly, the compound shows a good application prospect in the development of drugs for targeting human chronic myelogenous leukemia cells and human peripheral blood basophilic leukemia cells, and opens up a new field for the development of PROTAC drugs.

The invention relates to conjugates of biologically active compounds, wherein such a conjugate is comprised of a sequence of amino acids containing a tripeptide that confers selective cleavage by tumor tissue homogenate for release of free drug and / or improves biodistribution into the tumor tissue in comparison to normal tissue homogenate from the same species, wherein the normal tissue is the site of an adverse event associated with administration to a human subject in need thereof of a therapeutically effective amount of a comparator conjugate whose amino acid sequence is a dipeptide known to be selectively cleavable by Cathepsin B.

Compounds of the formula II:whereinR1 and R2 are independently H, F or CH3; orR1 forms an ethynyl bond and R2 is H or C3-C6 cycloalkyl which is optionally substituted with one or two substituents independently selected from methyl, CF3, OMe or halo;R3 is C1-C3 alkyl or C3-C6 cycloalkyl, either of which is optionally substituted with one or two methyl and / or a fluoro, trifluoromethyl or methoxy, when R3 is C3-C6 cycloalkyl it may alternatively be gem subsituted with fluoro;R4 is methyl or fluoro; m is 0, 1 or 2;E is a bond, or thiazolyl, optionally substituted with methyl or fluoro;A1 is CH or N,A2 is CR6R7 or NR6, provided at least one of A1 and A2 comprises N;R6 is H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C3 alkyl-O-C1-C3 alkyl, or when A2 is C, R6 can also be C1-C4 alkoxy or F;R7 is H, C1-C4 alkyl or For a pharmaceutically acceptable salt, N-oxide or hydrate thereof, have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.

The present disclosure provides an antibody-drug conjugate (ADC) having an antibody, antigen-binding fragment thereof, or cell-penetrating fragment thereof; a cathepsin cleavable linker; and an exatecan payload moiety. Compositions including the ADC and methods of using the ADC are also provided.