CN-121971429-A - Application of morin O in preparation of TEAD protein palmitoylation inhibitor

Abstract

The invention discloses an application of Phellinin O in preparation of a TEAD protein palmitoylation inhibitor, and relates to the technical field of molecular biology. The invention also provides a TEAD palmitoylation inhibitor and a method for screening the TEAD palmitoylation inhibitor in vitro. The invention discovers that the compound can be directly combined with a lipid binding pocket of TEAD1 protein to interfere with the post-translational palmitoylation modification level of the TEAD1 protein, thereby reducing the conformational stability and transcriptional activity of the TEAD1 and having wide application value.

Inventors

• ZOU CHENGGANG
• DUAN JIAHONG
• CUI YONGYI
• MA YICHENG

Assignees

• 云南大学

Dates

Publication Date

20260505

Application Date

20260407

Claims (9)

1. 1. Application of morin O in preparing TEAD protein palmitoylation inhibitor is provided.
2. 2. The use according to claim 1, wherein the chemical structure of the doxorubicine O is as follows: 。
3. 3. the use of claim 1, wherein the TEAD protein is TEAD1.
4. 4. The use of claim 1, wherein said morin O reduces the transcriptional activation of TEAD1 by binding to the conserved domain of the TEAD1-YBD protein, interfering with its specific post-translational modification.
5. 5. The use according to claim 1, wherein the moracin O inhibits its level of palmitoylation modification by binding to the palmitoylation pocket in the TEAD1-YBD protein domain.
6. 6. The use according to claim 1, wherein the inhibitor is an irreversible inhibitor.
7. 7. The use of claim 1, further comprising the use of a derivative of moracin O for the preparation of a TEAD protein palmitoylation inhibitor; The derivatives of the saminin O are compounds with the same functions, which are obtained by modification on the basis of the saminin O.
8. 8. A TEAD palmitoylation inhibitor, comprising the structure analogue of moracin O or moracin O as claimed in claim 1, wherein the structure analogue of moracin O is modified by a substituent on the basis of moracin O and retains the activity of inhibiting TEAD palmitoylation.
9. 9. A method for in vitro screening of a TEAD palmitoylation inhibitor, characterized in that a candidate small molecule compound is incubated with a TEAD1-YBD protein and its effect on the level of TEAD1 palmitoylation modification is detected, and that the moracin O as described in claim 1 is used as a positive control compound.

Description

Application of morin O in preparation of TEAD protein palmitoylation inhibitor Technical Field The invention relates to the technical field of molecular biology, in particular to application of a Phellinin O in preparation of a TEAD protein palmitoylation inhibitor. Background The TEAD (TEA domain) family of transcription factors, the core downstream regulatory elements in multiple signaling pathways, play an important role in regulating cell proliferation, stem maintenance and signaling. It was found that TEAD function was not only dependent on the co-activator binding such as YAP, TAZ, VGLL, but was also finely regulated by post-translational modification. Among them, palmitoylation modifications at TEAD key cysteine residues have been shown to have important effects on their structural stability, nuclear localization ability and DNA binding activity. Currently, studies have confirmed that TEAD proteins present stable lipid modification pockets and several small molecule inhibitors can affect the modification state of this site by high throughput screening. However, most of these inhibitors are synthetic compounds, lacking structural diversity and research tool attributes. Therefore, the natural small molecular compound with clear sources and stable structures is searched for the research of the mechanism of TEAD posttranslational modification and the construction of a small molecular screening system, and has important scientific value. Moracin O (Moracin O) is a natural flavonoid derived from Moraceae plants and its role in transcription factor regulation, especially protein post-translational modification has not been reported. Disclosure of Invention In order to solve the technical problems, the invention aims to provide an application of the morin O in preparing a TEAD protein palmitoylation inhibitor, wherein the compound can be directly combined with a lipid binding pocket of the TEAD1 protein to interfere with the post-translational palmitoylation modification level of the TEAD1 protein, so that the conformational stability of the TEAD1 is influenced and the transcriptional activity of the TEAD1 is reduced. The compound can be used as a research tool for researching a TEAD1 posttranslational modification mechanism, and is used for constructing a screening platform or used as a positive reference substance for mechanism verification. In addition, the moracin O can be used for researching the functional relation of TEAD1 protein in different signal paths, and has wide basic research value. The technical scheme for solving the technical problems is as follows, and the application of the Phellinin O in preparing a TEAD protein palmitoylation inhibitor is provided. Further, the chemical structure of the Phellinin O is as follows: 。 further, the TEAD protein is TEAD1. Further, the binding of the saminogen O to the TEAD1-YBD protein conserved domain interferes with its specific post-translational modification state, reducing TEAD1 transcriptional activation. Further, the moracin O inhibits its palmitoylation modification level by binding to the palmitoylation pocket in the TEAD1-YBD protein domain. Further, the inhibitor is an irreversible inhibitor. Further, the application also comprises application of the derivatives of the morin O in preparing TEAD protein palmitoylation inhibitors; the derivatives of the saminin O are compounds with the same functions, which are obtained by modification on the basis of the saminin O. The invention also provides a TEAD palmitoylation inhibitor which comprises the structure analogue of the moracin O or the moracin O, wherein the structure analogue of the moracin O is modified by a substituent group on the basis of the moracin O, and the TEAD palmitoylation inhibitor keeps and inhibits the TEAD palmitoylation activity. The invention also provides a method for screening TEAD palmitoylation inhibitor in vitro, which comprises the steps of incubating a candidate small molecule compound with TEAD1-YBD protein, detecting the influence of the candidate small molecule compound on the TEAD1 palmitoylation modification level, and using the saminogen O as a positive control compound. The invention has the following beneficial effects: Through virtual screening and further verification, the invention discovers that the morin O can be directly combined with a lipid binding pocket of TEAD1 protein to interfere with the post-translational palmitoylation modification level of the TEAD1 protein, thereby influencing the conformational stability of the TEAD1 and reducing the transcriptional activity of the TEAD1 protein. The function has important scientific value in post-translational modification regulation and control research, and is suitable for in-vitro experimental research and tool system development in the fields of molecular biology, protein modification mechanism, signal transduction and the like. Drawings FIG. 1 is a graph showing the experimental results of the effect of do