381 results about "Protein targeting" patented technology

The invention discloses a modified Trim 21 (delta Trim 21)-based target protein degradation control system, which takes a modified protein delta Trim 21 degradation system as a basis, takes blue light, abscisic acid, Danoprevir and / or MK-5172 as inductors, controls the combination of target protein and delta Trim 21 by introducing and modifying a controllable protein dimerization system on the basis of the modified protein delta Trim 21 degradation system, and improves the target protein degradation control system. The protein targeted degradation capable of being modularly regulated and controlled is carried out. Two regulation and control modules, namely a target protein recognition module and a degradation module based on E3 ubiquitinase, are constructed by splitting and recombining a controllable protein dimerization system and a delta Trim 21 structural domain. The invention also discloses a degradation device comprising the system. The invention also discloses a method for accurately regulating endogenous proteins (degradation of proteins related to tumorigenesis) by using the programmable regulation type modular protein degradation device, so as to achieve the effect of specifically killing tumors. The invention also provides a eukaryotic expression vector and a regulation method of the programmable regulation type protein targeted degradation device.

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that degrade and / or otherwise modulate (e.g., inhibit) NIMA Related Kinase 7 (NEK7). Said chemical entities are useful, e.g., for treating a subject (e.g., a human subject) having one or more disorders or diseases associated with NLRP3 inflammasome activation. Said disorders or diseases include but are not limited to, autoinflammatory and autoimmune disorders (e.g., gout, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), cardiovascular and metabolic disorders (eg. pericarditis, atherosclerosis, Type 2 diabetes, obesity, and metabolic syndrome), fibrotic disorders (e.g. interstitial lung disease, chronic kidney disease), hematology (eg. anemia of inflammation) and eye disorders (eg. macular degeneration). In embodiments, and while not wishing to be bound by theory, it is believed that the chemical entities described herein directly target (e.g., directly bind to) NEK7, thereby altering (e.g., attenuating) the inflammatory response modulated by the NLRP3 inflammasome. This disclosure also features compositions containing the same as well as methods of using and making the same.

The invention relates to the technical field of pharmacology and artificial intelligence, and provides a compound-target interaction prediction method and system, and the method comprises the steps: constructing a knowledge graph containing compounds, target entries and disease entities, and the correlation of the compounds, the target entries and the disease entities; inputting the knowledge graph into a multi-modal feature extraction model, and extracting topological information and internal semantic information in the knowledge graph; wherein the multi-modal feature extraction model comprises an ICD2Vec layer, a graph Transformer, a gene ontology embedding layer and an attention mechanism-based graph neural network, and the ICD2Vec layer, the graph Transformer, the gene ontology embedding layer and the attention mechanism-based graph neural network are respectively used for extracting disease semantic features, compound semantic features, protein target semantic features and topological features of a knowledge graph; performing knowledge fusion on the extracted semantic features and topological features of the knowledge graph through a feature fusion module, and obtaining a compound-target prediction probability matrix through a knowledge graph embedding method; and according to the compound-target prediction probability, performing descending sorting on the input compound-target interaction, and outputting a target recommendation list.

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. In some embodiments, the compounds of the invention “re-program” the binding of the presenter proteins to protein targets that either do not normally bind to the presenter protein (e.g., do not show detectable binding in mammalian cells absent the compound). In some embodiments, provided compounds “re-program” presenter protein binding to greatly enhance interaction with a particular target with which it may have some interaction absent the compound. Interactions achieved through such reprogramming result in an ability to modulate the activity of these new targets.

The invention provides a fibroblast activating protein targeting compound, a nuclide marker of the fibroblast activating protein targeting compound, a pharmaceutical composition containing the fibroblast activating protein targeting compound and application of the fibroblast activating protein targeting compound and the nuclide marker, and relates to the technical field of nuclide drugs. The fibroblast activating protein targeting compound comprises a compound shown as a formula I, and has remarkably enhanced tumor uptake and retention time. The invention also relates to a pharmaceutical composition and a kit containing the targeting compound, and application of the compound in diagnosis or treatment of fibroblast activating protein overexpression diseases. # imgabs0 #

The present disclosure relates to a novel class of bifunctional molecules that are useful in a targeted or selective degradation of a protein.

The invention discloses a PEI and targeting peptide modified magnetic nano-carrier and a preparation method and application thereof. The nano-carrier is regular in morphology and uniform in particle size and has good crystallinity and magnetic performance. E5 polypeptide and RGD cyclic peptide on the surface of the nano-carrier are respectively combined with CXCR4 protein and integrin on the surface of a tumor cell, and the nano-carrier and CXCR4 are internalized into lysosome through an integrin-mediated way, so that the target protein CXCR4 is degraded. The PEI in the nano-carrier can load and deliver siRNA into tumor cells to silence the expression of CXCR4 mRNA (messenger Ribonucleic Acid). Through nucleic acid delivery and a protein targeted degradation strategy, the CXCR4 level of tumor cells is jointly reduced, the migration ability of the tumor cells is inhibited, and meanwhile, the anti-tumor effect of M1 type polarization of macrophages is activated.

Provided are compounds that may bind a target protein, and result in modification of the target protein. The compounds may further bind a modifier protein. The modifier protein may carry out or enhance the modification of the target protein. The modification may activate or reactivate the target protein. Also provided are methods of using the compounds.

The invention discloses a shark source nano antibody targeting an FPV-VP2 protein and an application of the shark source nano antibody. The amino acid sequence of the complementarity determining region 3 of the shark source nano antibody is selected from any one of the sequences shown in SEQ ID NO.16 to SEQ ID NO.30, or a sequence having homology with the sequence shown in any one of the sequences shown in SEQ ID NO.16 to SEQ ID NO.30; the amino acid sequence of the shark source nano antibody is selected from any one of the sequences shown in SEQ ID NO.1-SEQ ID NO.15, or the amino acid sequence of the shark source nano antibody is selected from any one of the sequences shown in SEQ ID NO.1-SEQ ID NO.15, or a sequence having homology with the sequence shown in any one of the sequences shown in SEQ ID NO.1-SEQ ID NO.15. The shark source VNAR nano antibody has the advantages of small molecular weight, high affinity, high stability, easiness in genetic engineering modification, low production cost and the like.

The invention discloses an E3 ubiquitin enzyme mutant as well as modification and a protein targeted degradation system and application thereof, and particularly relates to a series of targeted protein degradation enhanced E3 ubiquitin enzymes (Trim21-N) and a modification method thereof, the E3 ubiquitin enzymes (Trim21-N) are obtained by modifying a wild type Trim21 (wtTrim21) protein structural domain, and the E3 ubiquitin enzymes comprise Trim21-a, Trim21-b, Trim21-c, Trim21-d, Trim21-e and Trim21-f. The efficiency of degrading the target protein through the ubiquitin proteasome is remarkably improved, and the method has the characteristics of strong endogenous and exogenous universality, high specificity, ubiquitin proteasome dependence, low cytotoxicity, strong cell compatibility and the like on the degradation of the target protein. The invention provides E3 ubiquitin enzyme (Trim21-N) based on a targeted protein degradation enhancement version and an exogenous fluorescence report degradation system of the E3 ubiquitin enzyme (Trim21-N), preferably Trim21-e with the optimal degradation effect, and the E3 ubiquitin enzyme (Trim21-N) is named as delta Trim21. The invention further provides an endogenous protein degradation system based on the delta Trim21. The method has the characteristics of high specificity, rapidness and small module, so that the method can be used for researching various biological and disease mechanisms, including the fields of cell targeted therapy, cell mechanism exploration, genetic engineering and the like.

The invention discloses application of an AI-driven target screening technology in anti-obesity treatment of a drug delivery system, and belongs to the field of cross fusion of biological medicine and artificial intelligence. The screening method provided by the invention comprises the following steps: selecting a signal channel target and active small molecules related to lipid metabolism; processing the signal channel target and the active small molecules through the data set to obtain an input matrix; and inputting the input matrix into a deep learning model to obtain the interaction intensity between the active small molecules and the signal path target. According to the method, an artificial intelligence technology is introduced, a deep learning model is constructed to efficiently predict the affinity between a drug and a protein target, the problems that a traditional target screening method depends on experience and is low in efficiency are solved, and target expression is subjected to experimental verification through a molecular biology method, so that the target screening efficiency is improved. A verification closed loop from calculation prediction to molecular demonstration is realized, and the biological credibility of a target screening result is proved.

The invention provides a method for predicting a compound target based on a compound perturbation transcriptome and a protein sequence and application, and the method creatively combines the characteristics of the compound perturbation transcriptome and the characteristics of the protein target sequence as input characteristics and combines a deep learning model to realize prediction of the compound target. Specifically, perturbation transcriptome and active and inactive target spot information data of a compound are collected, transcriptome features are extracted through principal component analysis and linear discriminant analysis, meanwhile, a protein language model is used for representing target spot protein features, the transcriptome and a target spot of the compound are converted into learnable embedding, and the target spot information of the compound is obtained. And the classification model is used for training and learning potential association of the two, and is finally used for compound target prediction. According to the method, an external test set is used for proving high accuracy and practical applicability of the model. The method has the advantages of being low in cost, high in efficiency and wide in range, the compound target spot discovery efficiency can be remarkably improved, and the research and development process of drugs can be accelerated.

The invention discloses methanogen lyase homologous with a PeiR lyase sequence and application of the methanogen lyase, and aims to solve the problem that PeiR lyase protein of a methanogen cell wall peptide bond can participate in a biological process of hydrolyzing archaea cell walls, effectively kill methanogen and reduce methane production, and protein homologous with the PeiR lyase protein has potential methane reduction potential. According to the invention, a series of biological information software is utilized to identify protein sequences coded by methanogens virus from rumen microbiome sequencing data, and sequence homology between the proteins and PeiR protein is further analyzed to obtain a series of methanogens lyases. In order to realize the expression of the lyase, multiple segments of primers are designed to synthesize a target sequence, and the target sequence is successfully expressed in a prokaryotic expression system. Through the detection of crude enzyme liquid, the effectiveness of the lyase in the aspect of reducing the methane yield is verified in an in-vitro gas production test.

Disclosed in the present invention is a novel substituted heterocyclic compound having VAV1 target degradation activity. Specifically disclosed is a compound serving as a VAV1 target degradation agent and having the structure of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, isotopic substituent or isomer of the compound. The compound can be used for preventing or treating diseases related to VAV1 targets or signaling pathways.

The invention relates to a bifunctional protein targeting PD-1 and TGF [beta] and application of the bifunctional protein in cancer treatment by combining radiotherapy. Specifically, the present invention relates to the use of a bifunctional protein targeting PD-1 and TGF [beta] in the preparation of a medicament for treating an individual suffering from cancer, the bifunctional protein targeting PD-1 and TGF [beta] comprising: (1) an anti-PD-1 antibody or an antigen binding fragment thereof; (2) an immunoglobulin Fc structural domain; and (3) a TGF-beta R II extracellular domain. The invention further relates to application of the PD-1 and TGF beta targeting bifunctional protein in preparation of drugs for treating or preventing lung diseases or symptoms, especially radiation-induced lung injury, caused by radiotherapy of individuals.

The invention discloses methanogen lyase homologous with high-dimensional characteristics of PeiW lyase and application of the methanogen lyase, and aims to solve the problem that PeiW lyase protein of methanogen cell wall peptide bonds can participate in the biological process of hydrolyzing archaea cell walls, effectively kill methanogen and reduce methane production, and protein homologous with the protein has potential methane reduction potential. According to the method, a series of bioinformatics software is utilized, a protein sequence coded by methanogens virus is identified from a large amount of rumen microorganism virus group sequencing data, the high-dimensional homology of a deep learning model between the protein sequence and PeiW is analyzed, and two methanogens lyases similar to the high-dimensional characteristics obtained by the PeiW model are obtained. In order to realize the expression of the lyase, multiple segments of primers are designed to synthesize a target sequence, and the target sequence is successfully expressed in a prokaryotic expression system. Through detection of a crude enzyme solution, the effectiveness of the lyase in the aspect of reducing the yield of methane is verified in an in-vitro gas production test.

The invention discloses an oligonucleotide intracellular nano delivery system based on polypeptide modification and application thereof. The system is composed of a periostin targeting sequence (SDSSD), a matrix metalloproteinase 2 (MMP2) response sequence (GPAGLLG), a cell penetrating sequence (RRRRRRRR, R9), a reactive oxygen species (ROS) scavenging and adhesion enhancing group (Gly-DOPA)) and a terminal dibenzocyclooctyne (DBCO) modified engineered polypeptide SDSSD-PEG5-YGFGG-GPAGLLG-R9-(G-DOPA) 3-K4-C-DBCO, and a target oligonucleotide miRNA-26a-A5-Azido modified by 5-polyadenylic acid (AAAAA) and an azide group (Azido), and the target oligonucleotide miRNA-26a-A5-Azido, the target oligonucleotide and assembling through a click chemical reaction and a non-covalent interaction. The nano system has good bone targeting, enzyme responsiveness, intracellular delivery effect and biological safety, can realize stable and efficient delivery of therapeutic oligonucleotides in vivo, and significantly improves the utilization efficiency and therapeutic potential of oligonucleotides. The oligonucleotide intracellular nano delivery system has a wide application prospect in the fields of clinical transformation and precise treatment of oligonucleotide drugs.

The invention relates to application of a vitamin E compound in preparation of a MACIR protein targeting agent. The vitamin E compound comprises any one or a combination of at least two of tocopherol, tocopherol derivatives, tocotrienol or tocotrienol derivatives. The invention creatively discovers the interaction between tocopherol, tocopherol derivatives, tocotrienol or tocotrienol derivatives and MACIR protein, and proves the strong binding capacity of tocopherol or derivatives thereof and MACIR protein through experiments. The tocopherol, the tocopherol derivative, the tocotrienol or the tocotrienol derivative can be used for regulating the function of MACIR protein associated immune cells so as to influence the expression of inflammatory factors, play an important role in inflammation and anaphylaxis, and also can be used for improving skin injury repair.

The present invention relates to a fibroblast activation protein alpha (FAP)-targeting conjugate comprising Formula I: Y-L-X, wherein Y is a chelator or cytotoxic drug, L is a linker, and X is a molecule comprising a cyclic peptide of formula A-[Z-AA1-AA2-AA3-AA4-AA5-AA6-AA7-Z]-B. A is N-terminal structure. B is C-terminal structure, and each of the Z, AA1, AA2, AA3, AA4, AA5, AA6, AA7 is a residue of an amino acid.

The invention discloses a nano degradation agent for targeted degradation of PI3Kalpha protein as well as a preparation method and application of the nano degradation agent. The nano degradation agent comprises a polyamidoamine dendritic polymer G3-NH2, a PI3Kalpha protein targeted receptor and an HSC70 protein targeted receptor, wherein the PI3Kalpha protein targeted receptor and the HSC70 protein targeted receptor are coupled to the surface of the polyamidoamine dendritic polymer G3-NH2. The prepared nano degradation agent enters cells in an endocytosis mode, specifically targets corresponding treatment targets after entering the cells, and then efficiently degrades PI3Kalpha protein through a molecular chaperone-mediated autophagy pathway of lysosome, so that the PI3Kalpha protein can be effectively degraded. The nano degradation agent provided by the invention can be applied to intervention of related diseases caused by PI3Kalpha protein abnormality.

The invention provides a drug target binding affinity prediction method and system based on a multi-level connection diagram, and relates to the technical field of computational biology, the method comprises the following steps: preprocessing drug small molecules, protein targets and affinity diagrams to obtain the multi-level connection diagram, and performing node feature extraction; obtaining drug isomorphic connection diagram embedding, drug internal connection diagram embedding, protein isomorphic connection diagram embedding, protein internal connection diagram embedding and heterogeneous connection diagram embedding; fusing the heterogeneous connection diagram embedding with the drug internal connection diagram embedding and the protein internal connection diagram embedding respectively to obtain drug internal connection diagram node features and protein internal connection diagram node features; and performing feature fusion based on an attention mechanism on the drug internal connection diagram node features, the protein internal connection diagram node features, drug isomorphic connection diagram embedding and protein isomorphic connection diagram embedding to obtain a drug-protein interaction feature input classifier, and outputting a prediction result of the drug target binding affinity.

The present disclosure relates to a novel class of bifunctional molecules that are useful in a targeted or selective degradation of a protein.

The present invention relates to a fibroblast activation protein alpha (FAP)-targeting conjugate comprising Formula I: Y-L-X, wherein Y is a chelator or cytotoxic drug, L is a linker, and X is a molecule comprising a cyclic peptide of formula A-[Z-AA1-AA2-AA3-AA4-AA5-AA6-AA7-Z]-B A is N-terminal structure. B is C-terminal structure, and each of the Z, AA1, AA2, AA3, AA4, AA5, AA6, AA7 is a residue of an amino acid.

The present invention relates to a pan-KRAS protein targeted modulator compound and the use thereof. Specifically, the present invention relates to a pan-KRAS protein targeted modulator compound as shown in general formula (A), a preparation method therefor, and the pharmaceutical use thereof.

The invention discloses an LbCas12a protein mutant as well as a preparation method and application thereof, the LbCas12a protein mutant is obtained by performing K390A or K945A mutation on a wild type LbCas12a protein, and the amino acid sequence of the wild type LbCas12a protein is as shown in SEQ ID NO. 1. According to the present invention, the LbCas12a protein is subjected to directional modification, the alanine mutation occurs at the K390 / K945 site, the LbCas12a-K390A protein mutant and the LbCas12a-K945A protein mutant are prepared, the protein mutants obtained based on the method provide a series of significant advantages in function, and the solid foundation is laid for the application of the protein mutants in multiple fields. Through Michaelis-Menten kinetic analysis, it is observed that when the LbCas12a-K390A / K945A protein mutant prepared through the method and the wild type LbCas12a protein target the same dsDNA target, the catalytic efficiency of the LbCas12a-K390A / K945A protein mutant is 42.1 times that of the wild type LbCas12a, and the catalytic efficiency of the LbCas12a-K390A / K945A protein mutant is 707.9 times that of the wild type LbCas12a, and the catalytic efficiency of the LbCas12a-K390A / K945A protein mutant is 707.9 times that of the wild type LbCas12a. The results show that K390 and K945 are mutated into alanine, so that the affinity of the LbCas12a protein to a substrate can be increased to a certain extent, and the LbCas12a protein has higher trans-cleavage activity.

The invention belongs to the technical field of medicines, and particularly relates to a PARP-1 protein targeted degradation chimera compound as well as a preparation method and application thereof. The PARP-1 protein targeted degradation chimera compound is as shown in a formula (I), wherein P represents a ligand of PARP protein, Z represents a ligand of E3 ligase, and L represents a middle connecting chain part; the compound can be used for treating or preventing tumors. The PARP-1 protein targeted degradation chimera disclosed by the invention has a relatively good inhibition effect on proliferation of tumor cells, has a very high degradation effect on PARP-1 protein, and has concentration gradient dependence. (I).

The invention provides an affinity prediction method based on local interaction of a pharmacophore and a target spot, and relates to the technical field of DTA prediction, and the method comprises the steps: constructing a molecular graph and a pharmacophore graph of a drug according to the structure of the drug, coding the pharmacophore graph through a graph neural network, and obtaining an embedded vector of the pharmacophore graph; updating messages among atoms by adopting a directional message passing neural network to obtain updated embedding characteristics of the medicines; processing the updated embedding characteristics of the medicine by adopting a multi-layer gating message passing neural network to obtain medicine substructure embedding characteristics; constructing a protein map, and processing the protein map by adopting a substructure perception map neural network to obtain protein substructure embedding features; a variational auto-encoder is adopted to simulate local interaction between drug molecules and a protein target, and a predicted value of affinity is obtained. By considering the spatial arrangement and pharmacophore information of the drug molecules, efficient and accurate prediction of the affinity of the drug and the target can be realized.

Virtual screening methods are disclosed for predicting interacting compounds, from a chemical library, for proteins. The methods using an Extremely Randomized Trees (Extra Trees) machine learning model in which parent node(s) represent a decision in relation to a target-compound complex, based on a plurality of features corresponding to a protein target of the complex and a plurality of features corresponding to a compound of the complex, and leaf nodes classify the target-compound complex as either interacting or non- interacting. The Extra Trees model outputs a probability that target-compound complex is interacting, based on aggregated classifications from each decision tree. Applying the Extra Trees model to a further protein target and compounds produces a probability that each compound will form an interacting complex with the further protein target. The compounds are then ranked based on the respective probabilities, and highest probability compounds are then explored using a docking model.

Provided herein are complexes, methods, and therapeutic uses for inducing and / or enhancing the ubiquitination of proteins such as NRF2 by beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC).

The invention belongs to the field of neurobiology and drug research and development, and discloses application of NR3A as a protein target in screening or preparing drugs for preventing and / or treating depression-like behaviors. According to the invention, the expression of NR3A in hippocampus is enhanced by stereotactic injection of adeno-associated virus containing Grin3a gene. A chronic constraint stress (CRS) is adopted to induce a depressive mouse, and a sucrose preference test (SPT), a forced swimming test (FST) and an open field test (OFT) are adopted for identification. The expression of proteins such as NR3A, calpain 2 (Calpain2), neuron nitric oxide synthase (nNOS), 3-nitrotyrosine (3-NT), an NLRP3 inflammation complex and the like is detected by WesternBlot; and performing DHE staining to detect reactive oxygen species (ROS). By enhancing hippocampus NR3A expression, depression-like behaviors induced by CRS can be improved, signal cascade activated by calcium is inhibited, ROS generation and 3-NT expression are reduced, and neuroinflammation driven by NLRP3 inflammasomes is inhibited. The NR3A participates in depression-like behaviors induced by CRS, and the mechanism of the NR3A is related to calcium homeostasis regulation, ROS generation and inflammatory response driven by NLRP3 inflammasomes.