36 results about "FKBP" patented technology

Methods and compositions for the rapid and reversible destabilizing of specific proteins using cell-permeable, synthetic molecules are described. Stability-affecting proteins, e.g., derived from FKBP and DHFR proteins are fused to a protein of interest and the presence or absence of the ligand is used to modulate the stability of the fusion protein.

The present invention provides compositions and methods for evaluating the likelihood that a tumor is sensitive to an mTOR inhibitor, e.g., rapamycin or a rapamycin analog. The invention provides FKBP proteins as biomarkers for predicting the likelihood that a tumor is sensitive to an mTOR inhibitor. The methods include assessing the expression or activity of an FKBP protein, e.g., FKBP 12, in a subject with a tumor or in a sample derived from a tumor. Additional biomarkers and biomarker combinations are also provided. The invention also provides kits containing, e.g., a validated antibody or ligand for assessing the expression or activity of an FKBP protein.

Methods and compositions for the rapid and reversible destabilizing of specific proteins using cell-permeable, synthetic molecules are described. Stability-affecting proteins, e.g., derived from FKBP and DHFR proteins are fused to a protein of interest and the presence or absence of the ligand is used to modulate the stability of the fusion protein.

Disclosed are methods and compositions that employ FKBP-L polypeptides for modulating angiogenesis and / or tumor metastasis. The FKBP-L polypeptides may be used for the treatment of disorders mediated by angiogenesis such as cancer.

Disclosed are methods and compositions that employ FKBP-L polypeptides for modulating angiogenesis and / or tumor metastasis. The FKBP-L polypeptides may be used for the treatment of disorders mediated by angiogenesis such as cancer.

The present invention is directed to complexes of the protein p27(Kip1) with proteins identified as interacting with p27(Kip1) by a yeast mating test. Specifically, the present invention is directed to complexes with p27(Kip1) and FKBP-12. The present invention is also directed to complexes of a derivative, fragment or analog of p27(Kip1) and a derivative, fragment or analog of FKBP-12. Methods of screening the complexes for efficacy in treating and / or preventing certain diseases and disorders, particularly hyperproliferative disorders, including cancer, neurodegenerative disease, autoimmune disease, are also provided.

The invention discloses the cloning, expression and uses of a chimeric fusion protein with superior chaperone and folding activities compared to the wild type chaperones. This invention relates to a chimeric fusion protein encoded by a recombinant DNA molecule comprising nucleotide sequences coding for a polypeptide binding segment of a non-human chaperone protein and nucleotide sequences coding for an FK506 binding protein (FKBP) or an FK506-binding-protein-like domain (FKBP-like domain). In particular, this invention relates to a chimeric fusion protein encoded by a recombinant DNA molecule comprising nucleotide sequences coding for a polypeptide binding segment of a non-human chaperone protein and nucleotide sequences coding for a human FKBP type peptidyl-prolyl-cis / trans isomerase (PPIase), methods of producing these chimeric fusion proteins and their uses as folding helpers in the production of other proteins and in the process of the production of vaccines or pharmaceuticals, and as folding helpers for performing immunoassays.

Novel rapamycin analogues and methods for their production with FKBP and / or MIP inhibitory activity with reduced mTOR inhibitory activity with therapeutic potential e.g. as bacterial virulence inhibitors.

The invention discloses an inducible base editing system and an application thereof. The base editing system is composed of inducible human source cytosine deaminase (A3A) and SpCas9 with single nick activity; the deaminase can be split on the basis of potential amino acid sites; rapamycin interacts with the N end and the C end of the amino acid resolution site through FRB / FKBP to recombine split deaminase, and basic group editing is completed through induction. According to the method, the base editing activity is controlled by constructing the inducible base editing system, so that off-target editing is reduced; meanwhile, the splitting design in the application does not reduce target editing, so that the splitting design can be used as a compensation strategy of protein mutation, and can be used in combination with the mutated deaminase to further reduce off-target editing.

Analogs of FK506 that do not bind FKBP-12 have been found to effectively promote nerve cell growth and regeneration, thereby speeding functional recovery of damaged nervous tissue and axonal regeneration without causing immunosuppression.

The invention relates to the field of biomedicine, and discloses a vector system for inducing apoptosis, wherein the vector system comprises Plasmid CMV-FKBP-tdTomato and Plasmid EF1[alpha]-FRBCaspase8-2A-BSD. The invention further discloses a preparation method of the vector system. The invention also discloses an application of the vector system. The vector system is simple in preparation process, can be locally imported and expressed at a specific part, is direct in system action and lesion organism method, is short in onset period, can shorten the research time, can independently control the marking and clearing processes, and is more intuitive in experiment result; therefore, the vector system disclosed by the invention can be widely applied to mechanism research and treatment strategy exploration of diseases, such as in-vivo lesion cell distribution research of the diseases and occurrence and treatment relationship research of lesion cells and the diseases.

Analogs of FK506 that do not bind FKBP-12 have been found to effectively promote nerve cell growth and regeneration, thereby speeding functional recovery of damaged nervous tissue and axonal regeneration without causing immunosuppression.

The invention discloses an establishment method of a programmed necrosis inducing system. The establishment method comprises the following steps: linking a target gene segment RIPK3-2*FKBP to lentiviral vector containing a Tet-On system, so that a system which can induce expression is constructed; co-transfecting a vector which is correctly sequenced and a lentiviral element vector into 293T cells, collecting virus liquid infected Hela cells and A549 cells, and implementing puromycin screening, so that a stable cell line is obtained; inducing stable expression of RIPK3-2*FKBP protein of the cells by adding doxycycline to a culture medium, and then adding a dimer so as to induce dimerization of RIPK3; and on the basis of Western blotting and related experimental technological means, analyzing an experimental result. The inducing system provided by the invention has the beneficial effects that programmed necrosis of cells is induced through the Dox (the doxycycline) and Idimer; the system is higher in sensitivity and efficiency and stronger in specification; and necrosis of the cells can be rapidly induced.

The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein). These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of intracellular target proteins. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of the targeted protein's activity.

Provided herein are methods for identifying a compound that modulates a Ryanodine receptor (Ryr). Fluorescence resonance energy transfer between an FKBP bound to an RyR and fluorescent derivatives of RyR binding partners (e.g., calmodulin) or domain-peptide biosensors is used to provide a readout dependent on the RyR functional state. The methods permit measurement of RyR present in a permeabilized cell or in a purified membrane.

The invention discloses the cloning, expression and uses of a chimeric fusion protein with superior chaperone and folding activities compared to the wild type chaperones. This invention relates to a chimeric fusion protein encoded by a recombinant DNA molecule containing nucleotide sequences coding for a polypeptide binding segment of a non-human chaperone protein and nucleotide sequences coding for an FK506 binding protein (FKBP) or an FK506-binding-protein-like domain (FKBP-like domain). In particular, this invention relates to a chimeric fusion protein encoded by a recombinant DNA molecule containing nucleotide sequences coding for a polypeptide binding segment of a non-human chaperone protein and nucleotide sequences coding for a human FKBP type peptidyl-prolyl-cis / trans isomerase (PPIase), methods of producing these chimeric fusion proteins and their uses as folding helpers in the production of other proteins and in the process of the production of vaccines or pharmaceuticals, and as folding helpers for performing immunoassays.

The inventors have determined that increasing the expression level or activity of FKBP-L polypeptide in a subject, which can be provided by expression of nucleic acids encoding FKBP-L or by providing FKBP-L polypeptides to a subject is advantageous for use in the treatment of obesity and obesity-related disorders. In particular increased expression or activity of FKBP-L polypeptide in a subject may be used to treat excessive weight gain (which can be characterised as obesity), glucose intolerance, diabetes and metabolic syndrome, which are closely linked to obesity and insulin resistance. FKBP-L can also be used as a biomarker for obesity and obesity-related disorders.

The present disclosure provides methods and reagents useful for analyzing protein-protein interfaces such as interfaces between a presenter protein (e.g., a member of the FKBP family, a member of thecyclophilin family, or PIN1) and a target protein. In some embodiments, the target and / or presenter proteins are intracellular proteins. In some embodiments, the target and / or presenter proteins are mammalian proteins.

Disclosed are compounds of Formula (I) and pharmaceutical compositions thereof for the treatment of disorders or diseases mediated by the mTOR pathway by more selective binding to FKBP12 in the FK506 binding protein (FKBP) group. Those compounds are useful for the treatment of age or aging related diseases, diabetes, cancer, and inflammation related disorders due to unusual pharmacokinetic profiles and enhanced pharmacodynamic selectivity in target FKBP.

A composition for binding FKBP proteins is disclosed, along with a method of treating conditions associated with neuronal degeneration, wherein said composition comprises a compound of formula I,wherein, R, R1, R2, R3 and X are as defined herein.

Novel rapamycin analogues and methods for their production with FKBP and / or MIP inhibitory activity with reduced mTOR inhibitory activity with therapeutic potential e.g. as bacterial virulence inhibitors.

Compounds of formula (I) and their pharmaceutical compositions are disclosed for use in treating mTOR pathway-mediated disorders or diseases via more selective binding to FKBP12 among the FK506-binding proteins (FKBPs). Due to their abnormal pharmacokinetic profiles and enhanced pharmacodynamic selectivity at target FKBPs, these compounds are useful in treating age-related or senescence-related diseases, diabetes, cancer, and inflammation-related disorders. [Formula 1] JPEG2026512047000312.jpg8368

EVs are being recognized as vectors for drug delivery. In particular. EV loading with targeting and therapeutic agents brings along an interesting opportunity to translate EVs into a bio-mimetic selective delivery system. Indeed. EVs constitute a physiological carrier being potentially less immunogenic than artificial delivery vehicles. The inventors now developed a novel method to control the loading of a cargo into EVs on demand. These EVs are equipped, if necessary, with non-viral fusogen, therefore enhancing EV-cargo delivery into acceptor cells. To acutely measure this process, they follow the fate of a luciferase-tagged cargo. Cargo loading was enabled through a drug-reversible inducible dimerization system. Briefly, donor cells were transfected with plasmids encoding for FKBP-tagged CD63, a classical membrane EV marker, and FRB-Nanoluciferase (NLuc) that is normally cytosolic. Upon addition of the dimerizing drug. FRB-Nluc interacts with FKBP-CD63 and is recruited into secreted EVs. This is accompanied by an enhanced delivery into acceptor cells. This phenomenon can be further enhanced when EVs are equipped with syncitin1, a mammalian fusogenic protein that trigger fusion between EV membrane and the plasma membrane of acceptor cells. Using this novel process, the inventors further demonstrated that the catalytic domain of the Diphteria toxin (DTA), that is responsible for protein synthesis inhibition and ultimately cell death, can be delivered to acceptor cells via functionalized EVs. This led to protein synthesis inhibition and death of acceptor cells. This novel method and the derived applications promise to open new doors in precision care medicine, especially when EVs will be equipped with antibodies raised against cell specific antigens.

The invention discloses an FK506 compound / FKBP protein dimer containing pharmaceutical composition and a preparation method thereof. FK506 and hFKBP12a protein in the FK506 compound / FKBP protein dimer containing pharmaceutical composition are combined according to a mass ratio of 1:1, and a PBS buffer solution with pH being 6-8 serves as a solvent. A dimer formed by FK506 and endogenous binding protein hFKBP12a of FK506 can greatly improve solubility of FK506 in a water solution, and accordingly efficacies of an FK506 water solution are enhanced while storage time of the FK506 water solution is prolonged.

The present invention discloses nano switch molecules and activation control solid tumor targeted CAR-T cells thereof. The solid tumor targeted CAR-T cells are prepared by the following steps of 1) preparing the nano switch molecules, wherein switch molecules are loaded on tumor targeted nanoparticles by adopting a double emulsification-volatilization method; 2) constructing assembled CAR-T plasmids, wherein T2A elements, FRB and FKBP sequences and solid tumor targeted ScFv fragments are introduced in CAR-T plasmids by using a genetic recombination method; 3) preparing assembled CAR-T cells, wherein the assembled CAR-T plasmids are transfected with T lymphocytes; and 4) preparing the solid tumor targeted CAR-T cells, wherein the assembled CAR-T cells endocytose the nano switch molecules. The switch molecules are loaded on the tumor targeted nanoparticles, so that the switch molecules can be specifically gathered on the tumor tissues; and FKBP and FRAP of CAR-T are connected by the switch molecules, so that two parts of CAR-T are combined to have the attack activity, and the problem of CAR-T cell off-target effect can be solved fundamentally.

A composition for binding FKBP proteins is disclosed, along with a method of treating conditions associated with neuronal degeneration, wherein said composition comprises a compound of formula I,wherein, R, R1, R2, R3 and X are as defined herein.

The present invention provides methods of limiting or preventing decreased levels of RyR2-bound FKBP 12.6 in a patient, methods of treating or preventing exercise-induced cardiac arrhythmias in a patient, and methods of preventing exercise-induced sudden cardiac death in a patient. Use of JTV-519 in these methods is also provided. The present invention also provides a method of identifying a substance for preventing exercise-induced sudden cardiac death, and a substance identified by the method. Also provided are methods of preventing exercise-induced sudden cardiac death by administering these substances. Additionally, the present invention provides methods for the synthesis of JTV-519, radiolabeled JTV-519, and 1,4-benzothiazepine intermediates and derivatives.

Compositions containing multiple different AAV stock are provided which allow for regulated expression of an immunoglobulin in a variety of tissues. Also provided is a method for regulating the dose of a pharmacologically active immunoglobulin. The method involves co-administering: (a) a first stock of recombinant AAV containing: an activation domain operably linked to expression control sequences comprising a promoter and a first nuclear localization signal; and a DNA binding domain comprising a zinc finger homeodomain and two or more FK506 binding protein domain (FKBP) subunit genes, wherein a first FKBP subunit gene and a second FKBP subunit gene have coding sequences which are no more than about 85% identical to each other, said DNA binding domain being operably linked to a second nuclear localization signal; and (b) a second stock of recombinant AAV comprising at least 2 to about 12 copies of a zinc finger homeodomain which are specific binding partners for the zinc finger homeodomain of the DNA binding domain, and further comprising at least one immunoglobulin expression cassette operably linked to inducible expression control sequences, such that when an effective amount of a rapamycin or rapalog is delivered transcription and expression of the immunoglobulin gene is induced.

The invention discloses the cloning, expression and uses of a chimeric fusion protein with superior chaperone and folding activities compared to the wild type chaperones. This invention relates to a chimeric fusion protein encoded by a recombinant DNA molecule comprising nucleotide sequences coding for a polypeptide binding segment of a non-human chaperone protein and nucleotide sequences coding for an FK506 binding protein (FKBP) or an FK506-binding-protein-like domain (FKBP-like domain). In particular, this invention relates to a chimeric fusion protein encoded by a recombinant DNA molecule comprising nucleotide sequences coding for a polypeptide binding segment of a non-human chaperone protein and nucleotide sequences coding for a human FKBP type peptidyl-prolyl-cis / trans isomerase (PPIase), methods of producing these chimeric fusion proteins and their uses as folding helpers in the production of other proteins and in the process of the production of vaccines or pharmaceuticals, and as folding helpers for performing immunoassays.