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CN-122005532-A - Application of caffeic acid phenethyl ester in preparation of ribosomal large subunit protein L1 targeted inhibitor

CN122005532ACN 122005532 ACN122005532 ACN 122005532ACN-122005532-A

Abstract

The invention discloses the technical field of biological medicines, and in particular relates to application of caffeic acid phenethyl ester in preparation of a ribosomal large subunit protein L1 targeted inhibitor. In the invention, through drug affinity induced target stability, the ribosomal large subunit protein L1 target inhibitor can directly target the ribosomal large subunit protein L1 in bacteria, and can be used as a competitive inhibitor to competitively bind with RRF to L1, inhibit the ribosome recovery process, inhibit the bacterial translation process and cause the inhibition and death of bacterial protein synthesis. The mechanism makes the ribosomal large subunit protein L1 become a ribosomal target with therapeutic potential, provides a new target and theoretical basis for clinical treatment of bacterial infection, and provides a new support for screening of new broad-spectrum antibiotics.

Inventors

  • LIU XIANGRUI
  • ZHAO WENBIN
  • ZHOU TIANHUA

Assignees

  • 浙江大学

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. The application of caffeic acid phenethyl ester in preparing a ribosomal large subunit protein L1 targeting inhibitor is characterized in that the ribosomal large subunit protein L1 targeting inhibitor inhibits the recovery process of a bacterial ribosome, inhibits the translation process of the bacteria and further inhibits or kills the bacteria by competitively combining with a ribosomal recovery factor with L1 protein; the bacteria include Bacillus cereus, listeria, streptococcus agalactiae, bacterial blight of rice, pathogenic bacteria of citrus canker, pseudomonas subtilis, salmonella and helicobacter pylori.
  2. 2. The use according to claim 1, wherein the ribosomal large subunit protein L1 targeted inhibitor is used for the preparation of antibacterial drugs or surface bactericides.
  3. 3. The use according to claim 1, wherein the amino acid sequence of the ribosomal large subunit protein L1 is shown in SEQ ID NO. 1.
  4. 4. The use according to claim 2, wherein the dosage form of the ribosomal large subunit protein L1 targeting inhibitor comprises an oral preparation, an injection preparation or an external preparation.
  5. 5. The method according to claim 2, wherein the surface bactericide is in the form of powder, granule, tablet, capsule, emulsion, water or aerosol.
  6. 6. Use of phenethyl caffeate as a ribosomal large subunit protein L1 targeting inhibitor in the preparation of a medicament for preventing bacterial infection.
  7. 7. The method of claim 6, wherein the bacteria include Bacillus cereus, listeria, streptococcus agalactiae, rhizoctonia solani, pathogenic bacteria of citrus canker, pseudomonas solanacearum, salmonella and helicobacter pylori.
  8. 8. Use of phenethyl caffeate as a ribosomal large subunit protein L1 targeting inhibitor in the preparation of a medicament for the treatment or co-treatment of bacterial infections.
  9. 9. The method according to claim 8, wherein the bacteria include Bacillus cereus, listeria, salmonella, streptococcus agalactiae, streptococcus dysgalactiae, rhizoctonia solani, pathogenic bacteria of citrus canker, pseudomonas solanacearum and helicobacter pylori.
  10. 10. A method for killing bacteria in vitro, comprising contacting a ribosomal large subunit protein L1 targeting inhibitor with an object to be sterilized, thereby inhibiting or killing bacteria thereon; wherein the ribosomal large subunit protein L1 targeting inhibitor is phenethyl caffeate; The bacteria include Bacillus cereus, listeria, salmonella, streptococcus agalactiae, bacterial leaf blight of rice, pathogenic bacteria of citrus canker, pseudomonas subtilis and helicobacter pylori.

Description

Application of caffeic acid phenethyl ester in preparation of ribosomal large subunit protein L1 targeted inhibitor Technical Field The invention relates to the technical field of biological medicines, in particular to application of caffeic acid phenethyl ester in preparing a ribosomal large subunit protein L1 targeted inhibitor. Background Antibiotics currently used clinically mostly act by inhibiting bacterial protein synthesis, and the main target is 30S or 50S subunits of ribosomes. For example, antibiotics such as chloramphenicol and macrolides act on the 50S subunit, interfering with peptide acyltransferase centers or nascent peptide chain channels, while tetracyclines and tigecycline bind the 30S subunit, affecting translation initiation or tRNA localization. However, bacteria can produce cross-resistance to these drugs through a variety of mechanisms such as rRNA modification, drug-modifying enzyme production, etc., resulting in failure of treatment based on these drugs. Therefore, the search for a protein synthesis link which is not targeted by the existing antibacterial drugs becomes an important direction for developing new mechanism antibiotics. The ribosome recovery process after translation termination is a key step for maintaining the translation cycle efficiency, and has not been fully developed as an antibacterial target at present. Ribosome recovery refers to the process of dissociation of 70S ribosomes into 30S and 50S subunits after translation termination, which consumes GTP and relies on the synergistic effect of elongation factor G (EF-G) and Ribosome Recovery Factor (RRF). The L1 protein in the 50S subunit forms the core of the L1 stalk, and its conformational change participates in the release of the deacylated tRNA from the E site. Although the role of RRF and EF-G in ribosome dissociation has been clarified, the mechanism of interaction between RRF and 50S subunit proteins (especially L1) is unclear, and whether the dynamic movement of the L1 handle and RRF function synergistically regulate the recovery process has yet to be elucidated. Revealing the molecular details of the process is expected to provide a new target for the development of antibacterial drugs. Helicobacter pylori (Helicobacter pylori) is a pathogenic bacterium colonizing the gastric mucosa and is closely related to the occurrence of chronic gastritis, peptic ulcer and gastric cancer. With the global spread of multiple drug-resistant strains of helicobacter pylori, the efficacy of traditional tetrad therapy for helicobacter pylori is increasingly decreasing. Meanwhile, the special population such as the elderly, children, pregnancy and the like has more limited types of optional antibiotics due to the limitation of pharmacokinetics and safety, so that the treatment of helicobacter pylori infection faces serious challenges. Therefore, there is a need to develop a novel broad-spectrum antibacterial agent for broad-spectrum killing of pathogenic bacteria, which has a novel mechanism of action, can avoid cross-resistance, realizes persistent clearance in refractory infections, and has good safety. Based on the current situation, the invention provides a new target for developing a broad-spectrum antibacterial drug by taking the ribosomal large subunit protein L1, and further discloses a new mechanism for inhibiting ribosome recovery, causing translation stagnation and bacterial death by blocking the combination of RRF and 50S subunits by specifically combining the key residues of the L1 protein by the ribosomal large subunit protein L1 targeting inhibitor, thereby providing a new direction and theoretical basis for the design and screening of novel antibacterial drugs. Disclosure of Invention The present invention aims to solve at least one of the above technical problems in the prior art. Therefore, the invention aims to provide a ribosomal large subunit protein L1 targeted inhibitor and application thereof. The invention discovers the application of the ribosomal large subunit protein L1 as a target for treating bacterial infection, reveals the therapeutic potential of the ribosomal large subunit protein L1 target inhibitor in treating bacterial infection, and researches the actual therapeutic effect and broad-spectrum antibacterial activity by taking one of the ribosomal large subunit protein L1 target inhibitors, namely caffeic acid phenethyl ester as an example. In the invention, through a drug affinity induced target stability experiment, the ribosomal large subunit protein L1 target inhibitor can directly target the ribosomal large subunit protein L1 in bacteria, can be used as a competitive inhibitor to competitively bind with RRF to L1, and can inhibit the ribosome recovery process, thereby inhibiting the bacterial translation process, and leading to the inhibition of bacterial protein synthesis and death. The mechanism makes the ribosomal large subunit protein L1 become a ribosomal target with therapeutic p