702 results about "Mutant protein" patented technology

Provided herein are compounds of Formula (I) or tautomers, atropisomers, stereoisomers, or pharmaceutically acceptable salts thereof. These compounds are useful as KRAS mutant degraders and / or inhibitors.

The present invention relates to a KRASG12D inhibitor and the use thereof. Specifically, provided in the present invention is a compound as shown in formula (I), and the definition of each substituent in the formula is as described in the description. In addition, the present invention further relates to a composition containing the inhibitor and the use thereof. The compound of the present invention has good tumor growth inhibitory activity, and has good safety.

Provided is an antibody-drug conjugate for use in the treatment of cancer in which one or more KRAS mutants, particularly a KRAS G12V mutant, a KRAS G12D mutant, and a KRAS G12C mutant, are expressed. Also provided are a drug and a drug-linker conjugate for use in the antibody-drug conjugate.　The present inventors have produced an antibody-drug conjugate with which a heterocyclic compound represented by formula (II) and having an activity of inducing the decomposition of KRAS mutant proteins can be delivered to cancer in which EGFRs are expressed, the production being achieved by linking the compound to an anti-EGFR antibody. The present inventors have also discovered a drug-linker conjugate for use in the antibody-drug conjugate or a salt thereof. In cancer in which EGFRs are expressed, the antibody-drug conjugate induces the decomposition of one or more KRAS mutants, particularly a KRAS G12V mutant protein, a KRAS G12D mutant protein, and a KRAS G12C mutant protein, thereby inhibiting the KRAS mutants and exhibiting an anti-tumor effect.

The invention discloses a mutant protein screening method and device and related equipment thereof, and relates to the technical field of material determination and analysis. The method comprises the following steps: respectively carrying out simulated single mutation on a plurality of amino acid sites in a protein sequence of a target protein to obtain a plurality of simulated mutant proteins, and determining adaptability evaluation values F of the plurality of simulated mutant proteins based on a target protein language model; determining structural stability values S of the plurality of simulated mutant proteins based on a protein folding energy calculation tool; performing normalization processing on the adaptability evaluation value F and the structural stability value S, and performing single-index sorting and comprehensive-index sorting on normalization processing results; and screening the plurality of simulated mutant proteins according to the target screening number, the single index sorting result and the comprehensive index sorting result to obtain a target mutant protein. According to the method, the protein design transformation difficulty can be reduced, the mutant protein screening effect is improved, the calculation amount required by protein transformation and screening is reduced, and the consumption cost is reduced.

The invention discloses a high-activity and high-thermal-stability MHET hydrolase mutant and application thereof. The invention provides a mutant protein of thermophilic carboxylesterase, which is shown as 1) or 2): 1) the protein shown as 1) is a protein obtained by mutating amino acid residues at the 130th site and the 171th site of wild thermophilic carboxylesterase shown as SEQ ID NO.2 or a sequence corresponding to the SEQ ID NO.2 and keeping other amino acid residues unchanged; (2) the protein is obtained by mutating amino acid residues at the 127th site, the 130th site and the 171th site of wild thermophilic carboxylesterase and keeping other amino acid residues unchanged. Experiments prove that the activity of the modified mutant for catalyzing MHET hydrolysis at the temperature of 50 DEG C is improved by 95 times compared with that of a wild type, and the modified mutant has higher enzyme activity and thermal stability and is the first enzyme capable of efficiently catalyzing MHET hydrolysis at the temperature of 50 DEG C at present.

The present disclosure provides compounds having activity as inhibitors of the G12C mutant KRAS protein, pharmaceutical compositions comprising the compounds, and methods of treating certain disorders, such as cancer, including but not limited to lung cancer, pancreatic cancer, colorectal cancer, and solid tumors. In particular, the disclosure provides compounds of Formula (I):, and pharmaceutically acceptable salts thereof, wherein the substituents are as described.

The present invention belongs to the technical field of bioengineering. Provided are an IscB mutein and the use thereof. Compared to the wild-type IscB protein, the IscB mutein comprises arginine at at least one of the following amino acid positions: position 84, position 96, position 102, position 111, position 159, position 368 and position 386; preferably, the IscB mutein further comprises arginine at position 401 and position 456. The relatively strong interaction between the IscB mutein and a double-stranded DNA target improves the editing activity for mammalian cell lines, which can greatly enhance the application potential of the IscB mutein as a new-generation underlying tool for gene editing, and promote the use of the IscB mutein in the aspects of precision medicine, animal model construction and crop breeding.

The invention discloses an optimized NlovFz2-omega RNA (Ribonucleic Acid) editing system, the optimal NlovFz2 system enNlovFz2 is obtained by modifying NlovFz2 protein and an omega RNA skeleton, and on the basis of remarkably improving the editing efficiency compared with a parent NlovFz2 system, the NlovFz2 mutant protein and T5 exonuclease are fused to obtain an enNlovFz2-T5 system with higher editing efficiency. The method has important significance and value for promoting wide application of a gene editing technology in the aspects of functional mechanism research and clinical treatment.

This disclosure describes a Machine Learning (ML) framework, including graph convolution neural networks (GCN) for identifying gene expression signatures related to cancer driver events. The model is trained to identify the TP53 mutational state of cancer samples from gene expression, utilizing comprehensive curated graph structures of gene interactions. A quantitative score is generated to rank the severity of a driver event in each sample. Very high AUG results on unseen data across several tumor types are achieved with this method. There is a strong correlation with protein function. The Signatures in Transcriptome Associated with Mutated Protein (STAMP) model can also predict driver events in many combinations of important cancer genes / pathways and several tumor types, based on well-established annotations from the literature. The STAMP model therefore can identify and quantify driver events, which may lead the way to improved targeted therapy selection and prioritization in cancer patients.

The invention belongs to the field of biological catalysis, and discloses a high-activity PET hydrolase mutant and application thereof. The mutant of the thermophilic PET hydrolase provided by the invention is as shown in 1), 2) or 3): 1) a protein corresponding to an amino acid sequence SEQ ID NO.4; 2) a protein corresponding to the amino acid sequence of SEQ ID NO.6; and 3) a protein corresponding to the amino acid sequence of SEQ ID NO.8. Experiments prove that the modified mutant shows higher catalytic efficiency on PET hydrolysis and can keep activity for a long time at the optimal temperature for PET depolymerization. The activity of the mutant protein BhrM3 for catalyzing PET hydrolysis is improved by 1.82 times compared with that of a wild type and is 1.22 times that of efficient PET hydrolase LCC-ICCG, and the protein melting temperature reaches 92.9 DEG C.

The present invention belongs to the field of nucleic acid editing, and particularly the technical field of clustered regularly interspaced short palindromic repeats (CRISPRs). Specifically, provided in the present invention is a Cas mutant protein having an improved activity and an improved editing efficiency. Compared with a wild-type parental Cas protein, the Cas mutant protein of the present invention has significantly improved activity, and has a wide application prospect.

The invention discloses an L-histidine transporter mutant and a method for increasing the yield of L-histidine, and the mutant has any one mutation of I20A, V28L, I20A-V28L and I20A-V21L-T28S relative to an escherichia coli wild type yeaS. The yield of the L-histidine of the recombinant escherichia coli containing the yeaS mutant protein is remarkably increased, it is indicated that the yeaS mutant protein and the coding gene of the yeaS mutant protein can be used for increasing the yield of the L-histidine, and the mutant can lay a good foundation for industrial efficient production of the L-histidine and downstream metabolites.

The invention provides a molecular modification method for glycosyltransferase based on artificial intelligence. The method comprises the following steps: acquiring description information of enzyme mutants to form a basic data set; performing physicochemical property analysis on the basic data set to obtain an analysis result set; calculating the quantized value of the conservative degree of the mutation site and the quantized value of the influence degree of different mutations on the sequence so as to construct a position specificity scoring matrix; extracting a position specificity scoring value and a frequency from the scoring matrix, determining a functional section, and performing weighting processing; performing three-dimensional structure prediction and energy calculation based on the three-dimensional structure reconstruction model of the mutant to obtain an energy value; calculating an energy change value between the mutant and the wild type; performing molecular docking and dynamic simulation analysis on the mutant protein to obtain quantitative description of an interaction mode and strength and dynamic simulation characteristic data; and constructing a model training set to train a machine learning model for predicting the change of the enzyme activity of the mutant.

The invention discloses an ochratoxin A degrading enzyme mutant and application thereof. The invention provides mutant protein of amidase MiADH, which is any one of the following changes: the amino acid sequence of the amidase MiADH as shown in SEQ ID NO: 1 is subjected to any one of the following changes: a 66th amino acid residue Y is mutated into K, or a 143rd amino acid residue H is mutated into A, or a 194th amino acid residue V is mutated into A, or a 195th amino acid residue L is mutated into A, or a 230th amino acid residue H is mutated into A, or the amino acid sequence of the amidase MiADH is mutated into A, or the amino acid sequence of the amidase MiADH is mutated into K, or the amino acid sequence of the amidase MiADH is mutated into A; or the 324th amino acid residue V is mutated into A, and the protein has the same function; experiments prove that the amide hydrolase MiADH mutant can efficiently degrade OTA, and OTA detoxification can be achieved under the high-temperature condition.

The invention relates to the technical field of tumor neoantigen detection, and particularly discloses a neoantigen prediction method and system for a malignant solid tumor, and the method comprises the following steps: obtaining a tumor sample and a peripheral blood sample, and carrying out DNA and RNA sequencing; analyzing and processing to obtain DNA (Deoxyribonucleic Acid) sequencing data and RNA (Ribonucleic Acid) sequencing data; analyzing to obtain an HLA typing result and a sequence of the mutant protein; calculating to obtain related characteristic values of the new antigens; calculating a new antigen score; and intercepting the first N pieces with the highest scores to obtain a neoantigen prediction result of the malignant solid tumor. Starting from the action mechanism of the new antigens, according to key steps of the prediction process, a plurality of characteristic values are selected, a hard filtering index is not adopted, a product mode is adopted, and the score of the new antigens is calculated according to the score of the relevant characteristic values of the new antigens.

The embodiment of the invention provides a protein stability prediction method and device, computer equipment and a storage medium. The method comprises the following steps: acquiring a first to-be-detected sequence corresponding to an original protein and a second to-be-detected sequence corresponding to a mutant protein; determining a plurality of first target residue features from the first to-be-detected sequence according to an attention mechanism of a protein language model, and extracting global features of the first target residue features to obtain first virtual structure microenvironment features; similarly, obtaining second virtual structure microenvironment features corresponding to a plurality of second target residue features; determining a first difference value based on the first virtual structure microenvironment feature and the second virtual structure microenvironment feature, and determining a second difference value based on a first global sequence feature corresponding to the first to-be-detected sequence and a second global sequence feature corresponding to the second to-be-detected sequence; and performing prediction according to the first difference value and the second difference value to obtain a protein stability prediction result. Therefore, the accuracy of predicting the stability of the protein can be improved.

The invention provides a nitrilase mutant and application of the nitrilase mutant in synthesis of p-cyanobenzoic acid. The invention provides a nitrilase mutant capable of improving the activity of catalytic synthesis of p-cyanobenzoic acid, the mutant protein is a non-natural protein, and the mutant protein can significantly improve the activity of catalyzing p-phthalonitrile to generate p-cyanobenzoic acid. And the mutant protein mutates in two or more core amino acids related to enzyme catalytic activity of the wild nitrilase. The nitrilase mutant provided by the invention can significantly improve the yield of a nitrilase catalytic synthesis product.

The invention discloses mutant protein of dihydroxyacetone phosphate phosphatase and application of the mutant protein. The invention provides a phosphodihydroxyacetone phosphatase mutant protein, which is characterized in that residues of phosphodihydroxyacetone phosphatase corresponding to 21st, 36th, 42nd, 49th, 64th, 82nd, 150th and 244th sites of an amino acid sequence shown in a sequence 1 are mutated to obtain a protein with phosphodihydroxyacetone phosphatase activity; and the synthesis capability of the 1, 3-dihydroxyacetone is improved. The invention also provides related biological materials and derivatives of the protein, and application of the protein in preparation of 1, 3-dihydroxyacetone. The yield of 1, 3-dihydroxy acetone of the protein is greatly increased, compared with starting wild type dihydroxy acetone phosphate phosphatase, the yield of 1, 3-dihydroxy acetone obtained through shake flask fermentation of the dihydroxy acetone phosphate phosphatase mutant SF6-11 is increased by 1.65 times, and the yield of 1, 3-dihydroxy acetone is increased to 4.54 + / -0.09 g / L from 2.75 + / -0.07 g / L.

The invention belongs to the field of nucleic acid editing, and particularly relates to the technical field of regularly clustered interval short palindromic repeat (CRISPR). Specifically, the invention provides a Cas mutant protein with improved activity and improved editing efficiency, and compared with a wild parent Cas protein, the Cas mutant protein disclosed by the invention has the advantages that the activity is obviously improved, and the Cas mutant protein has a wide application prospect.

The invention provides a carbonyl reductase mutant and an application of the carbonyl reductase mutant in synthesis of S-glassine. The mutant protein is a non-natural protein, and the mutant protein can significantly improve the activity of catalyzing the reduction of carbonyl in 1-C-(beta-D-xylopyranosyl)-acetone to generate S-configuration alcohol. When the activity-improved carbonyl reductase mutant strain is applied to the production process of S-configuration glassine, the carbonyl reduction capacity of the S-configuration glassine can be improved, 100-240 g / L of substrate can be completely converted, and the S-configuration glassine is generated.

The invention discloses a wheat mutant protein with glyphosate resistance, a gene and application thereof, and belongs to the technical field of plant breeding. The invention discloses wheat mutant proteins GR1 and GR19 with glyphosate resistance, six mutation sites and three mutation sites exist on an ESPSP protein respectively, and amino acid sequences of the 128 to 308 sites and amino acid sequences of the 133 to 308 sites are shown as SEQ ID NO. 4 and SEQ ID NO. 5 respectively. Two mutants with glyphosate resistance and excellent agronomic traits are found in a wheat mutant group by taking glyphosate as a screening agent, the two mutants are named as common wheat ZM9-GR1 and common wheat ZM9-GR19, and the invention discloses application of the mutants in plant breeding. The invention also discloses a method for cultivating glyphosate-resistant wheat by using the mutant for backcross breeding and cross breeding. The invention has important application value in plant breeding and agricultural production.

The invention relates to the technical field of biological genes, in particular to a rice herbicide-resistant OsEPSPS mutant gene, a protein and application thereof. The rice herbicide-resistant OsEPSPS mutant gene provided by the invention is characterized in that the 836th site of the nucleotide sequence of a wild rice OsEPSPS gene is mutated, and T is mutated into C. A plant containing the rice herbicide-resistant OsEPSPS mutant gene or the rice herbicide-resistant OsEPSPS mutant protein has remarkable resistance to glyphosate herbicide and can normally grow in the herbicide almost without being influenced, and under the same condition, the growth of a wild plant is remarkably inhibited until the wild plant dies, so that the rice herbicide-resistant OsEPSPS mutant gene or the rice herbicide-resistant OsEPSPS mutant protein has a good application prospect. The mutant gene and the mutant protein have huge market economic prospects.

The present application relates to a novel tricyclic derivative compound as a KRAS mutant protein inhibitor, and use thereof. The compound according to one embodiment of the present application inhibits the activity of a KRAS mutant protein and thus can be used in the prevention or treatment of diseases induced by KRAS mutation.

The invention discloses a dsPETase01 plastic degrading enzyme mutant and application thereof, and relates to the technical field of bioengineering, the amino acid sequence of a wild type plastic degrading enzyme (dsPETase01) is designed and modified, 8 dsPETase01 single mutation sites or 19 combined mutation sites are provided, the thermal stability of the obtained dsPETase01 mutant is improved by about 4-21 DEG C compared with that of the wild type dsPETase01, and the dsPETase01 mutant can be used for preparing a plastic degrading enzyme. And the activity is improved by nearly 1.2-3 times. The invention also provides four preferable mutant proteins which have higher yield, activity and thermal stability compared with wild dsPETase01, have wider application conditions, are more suitable for degrading PET (Polyethylene Terephthalate) plastics, and are beneficial to large-scale production and industrial application.

The present invention relates to the technical field of biomedicine. Specifically provided are a respiratory syncytial virus (RSV) Pre-F recombinant protein nanoparticle vaccine and a preparation method therefor. By performing amino acid mutation on an RSV Pre-F protein, and performing fusion expression on the mutated Pre-F protein and ferritin particles in eukaryotic cells, PreF-Ferritin fusion protein nanoparticles, in which eight Pre-F protein trimers are densely displayed on the surface of each ferritin particle, are obtained. By stabilizing and exposing antigen epitopes required to be displayed and disrupting or masking unrequired antigen epitopes, the PreF-Ferritin fusion protein nanoparticles effectively improve the immunogenicity and the production stability of the antigen. Experiments show that: when the PreF-Ferritin fusion protein is injected into mice, high-titer protective sera can be acquired, and the mice sera can yield relatively high neutralizing titers against RSV.

The invention discloses efficient expression of an aspergillus oryzae beta-galactosidase mutant and application of the aspergillus oryzae beta-galactosidase mutant in dairy products. The invention belongs to the technical field of enzyme engineering and the technical field of dairy product processing, and particularly relates to efficient expression of an aspergillus oryzae beta-galactosidase mutant and application of the aspergillus oryzae beta-galactosidase mutant in dairy products. The mutant protein disclosed by the invention can be as follows: A1) a protein with an amino acid sequence of SEQ ID No.2; a2) a fusion protein which is obtained by connecting a label to the N end and / or the C end of A1) and has the same function. The mutant protein is subjected to high-density fermentation in a 5L fermentation tank, the enzyme activity of fermentation liquor can reach 4628U / mL, and the recovery rate of mutant enzyme is increased by 1.7 times. Compared with a wild type, the mutant has the advantages that the optimum pH is increased from 4.5 to 5.5, the optimum temperature is reduced from 60 DEG C to 50 DEG C, the lactose hydrolysis efficiency is improved by 11%, and the mutant is more suitable for a production process of low / zero lactose dairy products.

The invention discloses Vip3 protein with improved activity and application thereof. Vip3Aa mutant protein is obtained by single-point mutation of a residue Y19 in a structural domain I or a residue V383 in a structural domain III; the Vip3Ca mutant protein is obtained by carrying out single-point mutation on a residue K383 in the structural domain III. The insecticidal activity of the Vip3 mutant protein disclosed by the invention on various lepidoptera pests is obviously improved compared with that of a wild protein.

The invention discloses a rice ACCase mutant protein and a preparation method thereof. The amino acid sequence of the ACCase mutant gene encoding protein has the following mutations: the 2052nd site corresponding to the amino acid sequence of wild rice ACCase is mutated, isoleucine (I) is changed into asparagine (N), or isoleucine (I) is changed into glutamine (Q), or isoleucine (I) is changed into cysteine (C), or isoleucine (I) is changed into cysteine (C), or isoleucine (I) is changed into cysteine (C), or isoleucine (I) is changed into cysteine (C), or isoleucine (I) is changed into cysteine (C). And the plant can have extremely strong resistance (tolerance) to acetyl-coenzyme A carboxylase inhibitor herbicides. After the rice containing the rice ACCase mutant protein disclosed by the invention is applied with an acetyl-coenzyme A carboxylase inhibitor herbicide with 8 times of recommended use concentration, plants still grow normally, and the tolerance of the herbicide is greatly enhanced, so that the rice ACCase mutant protein can be widely applied to breeding of herbicide-resistant plants.

The present invention relates to 4-1BB ligand (4-BBL) extracellular domain (ECD) muteins having reduce affinity for its cognate receptor 4-1BB. The 4-1BBL ECD muteins can be present in homo- or heterotrimeric fusion protein comprising three 4-1BBL ECD monomers. The invention further relates conjugates of such the 4-BBL ECD muteins with a heterologous moiety, such as an antigen binding protein. The antigen-binding regions comprised in the antigen binding protein in the conjugates preferably are specific for a tumor-associated antigen (TAA). In addition to a 4-BBL ECD mutein, the conjugates can comprise further NK cell-activating cytokines, such an IL-21 receptor agonist. The conjugates can further comprise an antigen-binding region that has affinity for a surface antigen expressed on NK cells, e.g. CD16A. Alternatively, the conjugates can further comprise an antigen-binding region that specifically binds an epitope of a γδ TCR. The conjugates of the invention specifically redirect and activate NK cells or γδ T cells to lyse targeted tumor cells. The invention further relates to the use of the 4-BBL ECD muteins and conjugates thereof in the treatment of cancer, preferably a cancer expressing the TAA.

Provided herein are methods of treating a KRAS mutant cancer (e.g., a KRAS G12C mutant cancer or a KRAS G12D mutant cancer) in a subject, comprising administering to the subject an effective amount of an agent that blocks the interaction between CD47 and SIRPα and an effective amount of a KRAS inhibitor (e.g., a KRAS G12C inhibitor wherein the cancer is a KRAS G12C mutant cancer, or a KRAS G12D inhibitor wherein the cancer is a KRAS G12D mutant cancer). Also provided are methods of stimulating phagocytosis of a population of cancer cells that express a KRAS mutant protein (e.g., a KRAS G12C mutant protein or a KRAS G12D mutant protein) by macrophages, comprising contacting the population with an effective amount of a therapeutic agent that blocks the interaction between CD47 and SIRPα and an effective amount of a KRAS inhibitor (e.g., a KRAS G12C inhibitor wherein the KRAS mutant protein is a KRAS G12C mutant protein, or a KRAS G12D inhibitor wherein the KRAS mutant protein is a KRAS G12D mutant protein).