751 results about "Mutated 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 invention relates to compounds of Formula I, II II-1, III, or III-1 and pharmaceutically acceptable salts thereof, and methods of making and using the same. The compounds of the invention are effective in inhibiting and / or degrading KRAS protein with a G12D mutation and are suitable for use in methods of treating cancers mediated, in whole or in part, by KRAS G12D mutation.

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.

Disclosed in the present invention are a quinazoline compound, and a pharmaceutical composition thereof and the use thereof. Provided in the present invention is a compound as represented by formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compounds of the present invention have a good degradation effect on the KRAS protein with a G12D mutation, have a good inhibitory activity against the proliferation of tumor cells with a KRAS G12D mutation, and exhibit good pharmacokinetic properties.

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.

Provided in the present invention are compounds shown as formula (I) and racemates, stereoisomers, tautomers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, which have good p53-Y220C mutant activation effect, can be used for treating tumor diseases containing p53-Y220C mutant proteins, and can be used for preparing drugs for such disorders or diseases.

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 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 present disclosure is in the field of plant genetic engineering. Specifically, the invention relates to application of a mutant GmLn protein and an encoding gene thereof in regulation and control of soybean yield, in particular to but not limited to a method for obtaining soybeans capable of being densely planted, a method for detecting the soybeans capable of being densely planted, related primers and kits, and further relates to soybean plants capable of being densely planted and a method for improving soybean planting density. According to the method provided by the invention, the soybean target sequence is subjected to gene editing by expressing the gene editing tool in the soybean, so that the soybean which is improved in yield and can be densely planted is obtained.

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 disclosure is directed to 4-pyrazolo[1,5-a]pyridin-2-yl-4, 5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine derivatives of formula (I) and pharmaceutically acceptable salts thereof, that stabilize phenylalanine hydroxylase (PAH) mutations, pharmaceutical compositions comprising those compounds, and methods of using those compounds in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.

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 Cas12j mutant protein with improved editing activity and application thereof, and the Cas12j mutant protein has a wide application prospect.

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 disclosure relates to compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ra, Rb, and x are defined herein, and pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt thereof.These compounds and pharmaceutical compositions are useful in methods for stabilizing a mutant PAH protein or reducing blood phenylalanine concentration in a subject suffering from phenylketonuria. In some embodiments, the mutant PAH protein contains at least one R408W, R261Q, R243Q, Y414C, L48S, A403V, I65T, R241C, L348V, R408Q, or V388M mutation. In other embodiments, the mutant PAH protein contains at least one R408W, Y414C, I65T, F39L, R408Q, L348V, R261Q, A300S, or L48S mutation.