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CN-121975770-A - Application of TREX1 protein non-substrate DNA binding interface as target spot in preparation of immune regulation medicine

CN121975770ACN 121975770 ACN121975770 ACN 121975770ACN-121975770-A

Abstract

The invention discloses an application of TREX1 protein non-substrate DNA binding interface as a target in preparing an immune regulation drug, and relates to the technical field of biological medicine. Wherein the TREX1 protein is a human TREX1 protein, and the non-substrate DNA binding interface comprises threonine at position 49, arginine at position 211, glutamine at position 213 and arginine at position 217 of the TREX1 protein. The invention discovers a non-substrate DNA binding interface in TREX1 for the first time, confirms the key role of the non-substrate DNA binding interface in maintaining immune homeostasis and tumor immune escape through mutation verification and functional analysis, and provides a novel anti-tumor immune strategy taking the non-substrate DNA binding interface as a target point. The discovery not only makes up the blank of TREX1 structure research, but also provides a new theoretical basis and a medicine development direction for immune regulation molecule design.

Inventors

  • ZHOU WEN
  • WANG LEI

Assignees

  • 南方科技大学

Dates

Publication Date
20260505
Application Date
20251223

Claims (10)

  1. The application of the TREX1 protein non-substrate DNA binding interface serving as a target spot in preparing an immune regulation medicament is characterized in that the TREX1 protein is a human TREX1 protein, the UniProt number of the TREX1 protein is Q9NSU2, and the non-substrate DNA binding interface comprises threonine 49 th, arginine 211 th, glutamine 213 th and arginine 217 th of the TREX1 protein.
  2. 2. The use according to claim 1, wherein the non-substrate DNA binding interface comprises threonine 49, glutamine 209 to arginine 217 of TREX1 protein.
  3. 3. The use according to claim 1, wherein the immune modulating drug is selected from one or more of a tumor immune modulating drug, an akadine-gully syndrome therapeutic drug, and a systemic lupus erythematosus therapeutic drug.
  4. 4. The application of the reagent for targeted disruption of the TREX1 protein non-substrate DNA binding interface in the preparation of immune regulation medicines is characterized in that the TREX1 protein is a human TREX1 protein, the UniProt number of the human TREX1 protein is Q9NSU2, and the non-substrate DNA binding interface comprises threonine 49, arginine 211, glutamine 213 and arginine 217 of the TREX1 protein.
  5. 5. The use according to claim 4, wherein the non-substrate DNA binding interface comprises threonine 49, glutamine 209 to arginine 217 of TREX1 protein.
  6. 6. The use according to claim 4, wherein the immune modulating drug is selected from one or more of a tumor immune modulating drug, an icaddy-curie syndrome therapeutic drug, and a systemic lupus erythematosus therapeutic drug; The reagent for targeted disruption of the TREX1 protein non-substrate DNA binding interface is selected from one or more of small molecules, nucleic acids, gene editing systems, proteins and polypeptides.
  7. 7. An immune regulation drug is characterized by comprising a reagent for targeted disruption of a TREX1 protein non-substrate DNA binding interface; Wherein the TREX1 protein is a human TREX1 protein, the UniProt number of the TREX1 protein is Q9NSU2, and the non-substrate DNA binding interface comprises threonine at position 49, arginine at position 211, glutamine at position 213 and arginine at position 217 of the TREX1 protein.
  8. 8. The immunomodulatory drug of claim 7 wherein the non-substrate DNA binding interface comprises threonine 49, glutamine 209 and arginine 217 of the TREX1 protein.
  9. 9. The immunomodulatory drug of claim 7, wherein the immunomodulatory drug further comprises pharmaceutically acceptable excipients; The route of administration of the immunomodulatory drug comprises a combination of one or more of oral, intravenous, intramuscular, and subcutaneous injection.
  10. 10. The immunomodulatory drug of claim 9, wherein the pharmaceutically acceptable excipients comprise one or more of pharmaceutically acceptable excipients, additives and adjuvants.

Description

Application of TREX1 protein non-substrate DNA binding interface as target spot in preparation of immune regulation medicine Technical Field The invention relates to the technical field of biological medicine, in particular to application of TREX1 protein non-substrate DNA binding interface as a target in preparation of an immune regulation medicine. Background TREX1 (THREE PRIME REPAIR exonuclease 1) is a 3 '. Fwdarw.5' exonuclease located in the plasma membrane, and is an important negative regulator for maintaining intracellular nucleic acid homeostasis and inhibiting innate immune abnormality activation. Its main function is to remove abnormally sourced DNA in the cytoplasm, including reverse transcription products, damaged DNA fragments, or non-timely degraded nucleic acid residues. By degrading these DNA, TREX1 prevents the sustained activation of cyclic GMP-AMP synthetase (CYCLIC GMP-AMP SYNTHASE, CGAS), thereby inhibiting abnormal expression of type I interferon mediated by the cGAS-STING (Stimulator of Interferon Genes) signaling pathway. Numerous studies have shown that TREX1 gene mutations can lead to cytoplasmic DNA clearance disorders, thereby eliciting chronic immune responses and interferon lesions. For example, TREX1 dysfunction is closely related to autoimmune diseases such as Aicarpi-Goutheres syndrome (AGS) and Systemic Lupus Erythematosus (SLE). Besides autoimmunity, TREX1 also has important regulatory effects in tumor microenvironments, and over-expression or abnormal localization of TREX1 can cause inhibition of anti-tumor immune response and promote tumor immune escape. Despite the intensive studies on the catalytic activity of TREX1 and its role in immune homeostasis, there is currently a lack of systematic understanding of the specific interface and molecular mechanisms by which it binds DNA. The existing crystal structure research is mainly focused on the catalytic core (DEDD nuclease domain) and reveals the degradation mechanism of the 3' -end of DNA substrate, but no clear structural evidence or functional explanation exists for the interaction interface of DNA outside the catalytic center, especially the binding mechanism of non-substrate strand DNA. Accordingly, the prior art is subject to improvement and development. Disclosure of Invention In view of the above-mentioned shortcomings of the prior art, the present invention aims to provide an application of TREX1 protein non-substrate DNA binding interface as a target in preparing immune regulation drugs, and aims to provide a new strategy for treating TREX1 related diseases by using a newly discovered non-substrate DNA binding interface (DNA B-site) in human TREX1 as a new target of immune regulation. The technical scheme of the invention is as follows: In the first aspect, the application of a TREX1 protein non-substrate DNA binding interface serving as a target in preparing an immune regulation medicament is provided, wherein the TREX1 protein is a human TREX1 protein, the UniProt number of the human TREX1 protein is Q9NSU2, and the non-substrate DNA binding interface comprises threonine at position 49, arginine at position 211, glutamine at position 213 and arginine at position 217 of the TREX1 protein. In a preferred technical scheme, the TREX1 protein non-substrate DNA binding interface is used as a target spot in the application of preparing an immune regulation medicament, wherein the non-substrate DNA binding interface comprises threonine at position 49 and arginine from position 209 to position 217 of the TREX1 protein. The preferred technical scheme is that the TREX1 protein non-substrate DNA binding interface is used as a target point in the application of preparing an immune regulation drug, wherein the immune regulation drug is selected from one or more of a tumor immune regulation drug, an Aikadi-Guttrium syndrome treatment drug and a systemic lupus erythematosus treatment drug. In a second aspect, the application of a reagent for targeted disruption of a TREX1 protein non-substrate DNA binding interface in preparation of an immune regulation drug is provided, wherein the TREX1 protein is a human TREX1 protein, the UniProt number of the TREX1 protein is Q9NSU2, and the non-substrate DNA binding interface comprises threonine 49 th, arginine 211 th, glutamine 213 th and arginine 217 th of the TREX1 protein. In a preferred technical scheme, the reagent for targeted disruption of the TREX1 protein non-substrate DNA binding interface is applied to preparation of an immune regulation drug, wherein the non-substrate DNA binding interface comprises threonine at position 49 and arginine from position 209 to position 217 of the TREX1 protein. According to a preferred technical scheme, the reagent for targeted disruption of the TREX1 protein non-substrate DNA binding interface is applied to preparation of an immune regulation drug, wherein the immune regulation drug is one or more selected from tumor immune regulation drugs