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CN-122011115-A - Cyclic antibacterial peptide derivative and application thereof

CN122011115ACN 122011115 ACN122011115 ACN 122011115ACN-122011115-A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to design, preparation and application of an antibacterial peptide derivative. The invention designs and prepares a series of cyclic peptide derivatives with symmetrical ends and beta-corner structures by taking P-07 antibacterial peptide as a structural template. The cyclopeptide derivative has higher antibacterial activity and safety, and has good application prospect in antibacterial aspect.

Inventors

  • MENG QINGBIN
  • WANG TAORAN
  • TIAN LONG
  • NING ZIYAO

Assignees

  • 中国人民解放军军事科学院军事医学研究院

Dates

Publication Date
20260512
Application Date
20260108

Claims (10)

  1. 1. A derivative antibacterial peptide based on P-07, which has an amino acid sequence shown in a general formula (1), (2) or (3): ZZ is selected from the beta-turn sequence WWW or PWWWP; each X 1 , which is identical or different, is selected independently of the others from basic amino acids or basic amino acid derivatives, which may be selected, for example, from lysine (Lys, K); Each X 2 , which is the same or different, is independently selected from a hydrophobic amino acid or a hydrophobic amino acid derivative, for example may be selected from isoleucine (Ile, I); Each Y, which is identical or different, is independently selected from amino acids which can be used to form covalent cross-links between side chains or amino acid derivatives which can be used to form covalent cross-links between side chains, and can be selected, for example, from cysteine (Cys, C), glutamic acid (Glu, E), lysine (Lys, K).
  2. 2. The antimicrobial peptide of claim 1, wherein the amino acid or amino acid derivative is L-or D-form.
  3. 3. Antibacterial peptide according to claim 1 or 2, characterized in that the antibacterial peptide N-terminal group is a free amino group or has been acetylated, for example N-terminal group is an acetamido group; Preferably, the C-terminal group of the antimicrobial peptide is carboxyl or amidated, for example, the C-terminal group is amidated to an amide group.
  4. 4. The antimicrobial peptide of claim 1, wherein the antimicrobial peptide has an amino acid sequence as shown in the following table: Note that a D amino acids are indicated in lowercase letters, b cyclization sites are indicated by asterisks; preferably, the antimicrobial peptide further comprises a pharmaceutically acceptable salt thereof.
  5. 5. The method for producing an antibacterial peptide according to any one of claims 1 to 4, which is produced by a solid phase synthesis method.
  6. 6. An antibacterial drug comprising a therapeutically effective amount of the antibacterial peptide of any one of claims 1-4; Preferably, the antibacterial drug is an external preparation, an oral preparation, an injection preparation or an inhalation preparation; Preferably, the oral preparation is selected from tablets, capsules, granules, powder, pills, oral liquid, syrup or drops, the injection preparation is selected from injection, powder for injection or concentrated solution, the external preparation is selected from ointment, cream, gel, patch, spray or lotion, and the inhalation preparation is selected from inhalation powder mist, aerosol or spray; Preferably, the antibacterial drug further comprises at least one pharmaceutically acceptable excipient; Preferably, the excipient comprises buffers, preservatives, stabilizers, binders, lubricants, chelating agents, dispersants, disintegrants, flavouring agents, diluents, surfactants, sweeteners and/or colouring agents.
  7. 7. Use of an antimicrobial peptide according to any one of claims 1 to 4 for the preparation of an antimicrobial medicament.
  8. 8. Use according to claim 7, wherein the antibacterial agent is for the prevention or treatment of infections caused by pathogens, such as skin wound infections; the bacteria are selected from gram positive bacteria or gram negative bacteria, such as at least one selected from staphylococcus aureus, enterococcus faecalis, staphylococcus epidermidis, escherichia coli, acinetobacter baumannii, klebsiella pneumoniae or multi-drug resistant strains thereof.
  9. 9. A composition comprising, as active ingredients, a therapeutically effective amount of the antibacterial peptide of any one of claims 1 to 4 and an antibacterial antibiotic; preferably, the combination antibacterial agent is for the treatment of infections caused by pathogens, such as skin wound infections; Preferably, the antibiotic is at least one selected from the group consisting of polypeptide antibiotics, penicillin antibiotics, beta-lactam antibiotics, quinolone antibiotics, cephalosporin antibiotics, and semisynthetic carbapenem antibiotics; Preferably, the pathogen is selected from gram positive or gram negative bacteria, for example from at least one of staphylococcus aureus, enterococcus faecalis, bacillus subtilis, staphylococcus epidermidis, pseudomonas aeruginosa, escherichia coli, acinetobacter baumannii, klebsiella pneumoniae, klebsiella aerogenes, streptococcus, bacillus or multi-drug resistant strains thereof.
  10. 10. The composition of claim 9, wherein the antimicrobial peptide is antimicrobial peptide PT-17.

Description

Cyclic antibacterial peptide derivative and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a cyclic antibacterial peptide derivative and application thereof in antibacterial aspect. Background At present, the propagation of multidrug-resistant bacteria caused by antibiotic abuse has become a global public health crisis, and development of novel antibacterial drugs is urgently needed. Unlike traditional antibiotics with specific molecular targets, the antibacterial peptide mainly plays a role in sterilizing by physically destroying bacterial membranes, and the action mechanism enables the antibacterial peptide to have broad-spectrum drug-resistant bacteria resistance, not easy to induce bacterial drug resistance and has great application potential. However, antibacterial peptides are susceptible to degradation by proteases in physiological environments, leading to rapid inactivation in the in vivo circulation, and limited clinical applications. P-07 (KIKIKPWWWPKIKIK-NH 2) is a beta-turn antibacterial peptide with a central beta-turn sequence (PWWWP) as a core, and cation/hydrophobic residue alternating extension fragments (KIKIK) which are symmetrically arranged on two sides. The antibacterial peptide plays a broad-spectrum antibacterial role through a membrane destruction mechanism, wherein tryptophan residues (WWW) which are continuously distributed in a beta-corner region can be anchored on the surface of a bacterial membrane strongly through hydrophobic and hydrogen bond interactions between indole ring side chains and bacterial membrane phospholipids, lysine residues at the tail end are electrostatically attracted with negatively charged membrane components by virtue of positive charges, and isoleucine is used for synergistically promoting the adsorption and insertion process of peptide segments on the membrane through the hydrophobic interaction. P-07 not only has stronger activity of resisting drug-resistant bacteria, but also has lower hemolytic property and cytotoxicity. In addition, the combination of the P-07 and the levofloxacin can effectively inhibit bacteremia infection caused by drug-resistant escherichia coli, and has higher clinical application potential. At present, the enzymolysis resistance stability of P-07 is still to be further improved. Disclosure of Invention In order to improve the enzymolysis stability of the P-07, the invention adopts cyclization and D-amino acid substitution strategies to carry out structural optimization on the beta-corner antibacterial peptide P-07. The cyclization strategy and the D-amino acid substitution strategy can interfere the recognition and degradation of protease by shielding protease cleavage sites and changing the chiral environment of amino acids at key sites, so that the enzymolysis resistance stability of the antibacterial peptide is enhanced. The invention provides a derivative antibacterial peptide based on P-07, which has an amino acid sequence shown in any one of general formulas (1), (2) or (3): According to an embodiment of the invention, ZZ is selected from the β -turn sequence WWW or PWWWP; According to an embodiment of the invention, each X 1, identical or different, is independently selected from basic amino acids or basic amino acid derivatives, which may be selected, for example, from lysine (Lys, K); according to an embodiment of the invention, each X 2, identical or different, is independently selected from hydrophobic amino acids or hydrophobic amino acid derivatives, for example may be selected from isoleucine (Ile, I); According to an embodiment of the invention, each Y, which is identical or different, is independently selected from amino acids or amino acid derivatives which can be used to form covalent cross-links between side chains, which can be selected from cysteine (Cys, C), glutamic acid (Glu, E), lysine (Lys, K), for example, wherein the side chains of two cysteines form disulfide bonds and the side chain of one glutamic acid forms an amide bond with the side chain of one lysine. According to an embodiment of the invention, the amino acid or amino acid derivative is in the L-or D-form. According to an embodiment of the invention, the N-terminal group of the antimicrobial peptide is a free amino group or is acetylated, for example the N-terminal group is an acetamido group. According to an embodiment of the invention, the C-terminal group of the antimicrobial peptide is carboxyl or amidated, for example, the C-terminal group is amidated to an amide group. According to an embodiment of the invention, the antimicrobial peptide is derived from P-07, obtained by D-amino acid substitution optimization and cyclization treatment. According to a preferred embodiment of the present invention, the antimicrobial peptide has an amino acid sequence as shown in table 1: TABLE 1 antibacterial peptide sequences and molecular weights according to preferred embod