A polypeptide, and its pharmaceutically acceptable salts or its enantiomers and applications

Abstract

The present application provides a kind of polypeptide and its pharmaceutical salt or its enantiomer and application.The polypeptide provided by the present application at least includes the fragment as shown in formula 1, specifically selected from at least one of A1) to A18).The polypeptide provided by the present application has excellent antibacterial activity, and has small toxicity, can be applied to various stubborn infectious diseases and common infections, as the excellent replacement drug or auxiliary drug of existing antibiotics.

Description

Technical Field

[0001] This invention relates to the field of polypeptide technology, and in particular to a polypeptide, its pharmaceutical salt or its enantiomer, and its applications. Background Technology

[0002] Cationic antimicrobial peptides, as a novel class of microbial killing agents, differ from traditional antibiotics in their mechanism of action. They target the biofilm system of pathogenic fungi / bacteria. The aggregation of antimicrobial peptide molecules on the biofilm increases biofilm permeability and causes the biofilm to lose its barrier function, thus killing fungi / bacteria. The development of drug resistance requires substantial alterations to the lipid composition of microbial cell membranes; therefore, it is virtually impossible for antimicrobial peptides targeting these membrane activities to develop resistance.

[0003] Cationic antimicrobial peptides are mainly classified into two categories: α-helical and β-sheet antimicrobial peptides. β-sheet antimicrobial peptides include cyclic polypeptides anchored by intramolecular disulfide bonds, such as aprotinins and protectins, as well as polypeptides with covalent bonds from the N-terminus to the C-terminus, such as bacitracin S and bacitracin. Unlike β-sheet antimicrobial peptides, α-helical antimicrobial peptides are more linear molecules that exist in a disordered structure in aqueous media. However, they exhibit an amphiphilic helical state through interactions with hydrophobic cell membranes, such as mothropol, magganin, and meliostepin.

[0004] Cationic antimicrobial peptides possess unique structural sequences, mechanisms of action, and highly effective bactericidal properties, making them different from traditional antibiotics. They are less prone to inducing drug resistance and exhibit virtually no cross-resistance with traditional antibiotics. Therefore, cationic antimicrobial peptides have broad clinical demand as excellent alternatives to traditional antibiotics. Developing new cationic antimicrobial peptides with even better antimicrobial activity remains a key focus in this field. Summary of the Invention

[0005] This invention provides a polypeptide, its pharmaceutical salt, or its enantiomer and its applications.

[0006] In a first aspect, the present invention provides a polypeptide, or a pharmaceutical salt thereof, or an enantiomer thereof, said polypeptide comprising at least a fragment with the structure shown in Formula 1:

[0007] X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X23 X 24 Equation 1; In Equation 1, X1 is selected from one of Lys, Dab, Ala, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X2 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X3 is selected from one of Dab, Ser, Ala, Lys, Thr, and Leu; X4 is selected from one of Ser, Lys, Dab, Thr, Ala, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X5 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X6 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X7 is selected from one of Dab, Lys, Ser, Ala, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X8 is selected from Thr, Ser, and Ala; X9 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X 10 Selected from one of Ser, Thr, Ala, Dab, Lys, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 11 Selected from one of Dab, Ala, Thr, Ser, Lys, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 12 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 13 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 14 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 15Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 16 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 17 Selected from one of Leu, Ala, Ser, Trp, Phe, Ile, Val, Nle, Nva, Dab, Lys, Thr; X 18 Selected from one of Dab, Ala, Lys, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 19 Selected from one of Thr, Lys, Leu, Dab, Ala, Ser, Trp, Phe, Ile, Val, Nle, and Nva; X 20 Selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X 21 Selected from one of Leu, Lys, Dab, Ala, Trp, Phe, Ile, Val, Nle, Nva, Ser, Thr; X 22 Selected from one of Dab, Ser, Ala, Lys, Thr, and Leu; X 23 Selected from one of Ala, Leu, Dab, Ser, Lys, Thr, Trp, Phe, Ile, Val, Nle, and Nva; X 24 Selected from one of Leu, Ser, Ala, Trp, Phe, Ile, Val, Nle, Nva, Thr; When the amino acid sequence of the polypeptide is Lys-Leu-Dab-Ser-Leu-Leu-Dab-Thr-Leu-Ser-Dab-Ala-Lys-Ala-Ala-Lys-Leu-Dab-Thr-Leu-Leu-Dab-Ala-Leu, the amino acids Dab at positions 3, 7, 11, and 22 are all of type D.

[0008] The polypeptide provided by this invention is based on the amino acid composition Lys D -Leu D -Dab L -Ser D -LeuD -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D It is derived from the antimicrobial peptide (Reference Journal of Medicinal Chemistry 2019, 62, 3354-3366, code D102). The derivatization methods include, but are not limited to: substitution of amino acid types, conformational changes, and extension or truncation of peptide sequences. The derived peptide has higher antimicrobial activity, or higher safety and antimicrobial specificity compared to D102.

[0009] The polypeptide provided by this invention has a suitable charge number at a pH value in an aqueous solution in a non-precipitated state, and contains both hydrophobic residues and residues with side-chain basic amino groups. It is amphiphilic and can be induced or pre-formed into a secondary structure (α-helix or β-sheet) that separates the hydrophobic residues from the residues with side-chain basic amino groups.

[0010] The polypeptide provided by this invention exhibits a certain α-helix structure in a hydrophobic environment, while possessing very little α-helix structure in a hydrophilic environment. This structural feature may be significant for the antibacterial activity mechanism of the polypeptide, for example: a) reducing the ability to form polymers in a hydrophilic environment, i.e., self-interaction ability; b) allowing the polypeptide molecule to more easily cross the cell wall and reach the cell membrane of microorganisms. Furthermore, the disruption of the α-helix structure in the hydrophilic environment does not affect the electrostatic attraction between the polypeptide (positively charged) and the cell wall of the microorganism (negatively charged); however, the lack of this specific structure can reduce the affinity of the cell wall surface for the polypeptide (the hydrophobic interaction between the hydrophobic groups in the cell wall and the hydrophobic surface of the polypeptide), thereby allowing the polypeptide to more easily pass through the cell wall and enter the hydrophilic / hydrophobic critical facet of the cell membrane, where the polypeptide is parallel to the membrane surface. Inside the membrane, the polypeptide can be induced into an α-helix structure by the hydrophobic environment of the cell membrane. Because of this α-helix structure, we hypothesize that the nonpolar side of the antimicrobial peptide can interact with the hydrophobic portion of the cell membrane, while the polar groups and positively charged groups on its polar side can interact with the polar (negative) heads of phospholipids on the cell membrane surface.

[0011] When a polypeptide has an α-helix structure, it exhibits characteristics of being net positively charged and amphiphilic. For example, an α-helix polypeptide has a nonpolar or hydrophobic surface on one side of the molecule and a polar or positively charged surface on the other side, i.e., an amphiphilic molecule.

[0012] In one specific embodiment, the polypeptide includes at least a fragment with the structure shown in Formula 2: KLX3X4LLX7X8LX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 LX 21 X 22 X 23 X 24 Formula 2; In Equation 2, K represents a lysine residue, L represents a leucine residue, and the rest of the definitions are the same as in Equation 1.

[0013] In one specific embodiment, in formula 1 or formula 2, X3 is selected from one of Dab, Ser, and Ala; X4 is selected from one of Ser, Lys, and Dab; X7 is selected from either Dab or Lys; X8 is selected from Thr or Ser; X 10 Selected from one of Ser, Thr, or Ala; X 11 Selected from one of Dab, Ala, or Thr; X 12 Selected from one of Ala, Lys, or Dab; X 13 Selected from one of Ala, Lys, or Dab; X 14 Selected from one of Ala, Lys, Dab, and Thr; X 15 Selected from one of Ala, Lys, or Dab; X 16 Selected from one of Ala, Lys, Dab, Thr, and Leu; X 17 Choose one of Leu, Ala, or Ser; X 18 Selected from one of Dab, Ala, and Lys; X 19 Selected from one of Thr, Lys, and Leu; X 21 Selected from one of Leu, Lys, and Dab; X 22 Choose one of Dab or Ser; X 23 Selected from either Ala or Leu; X 24 Selected from Leu and Ser.

[0014] In one specific embodiment, the polypeptide includes at least a fragment with the structure shown in Formula 3: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 SS type 3; In Equation 3, S represents a serine residue, X1-X 24 The definition is the same as in Equation 1.

[0015] In one specific embodiment, the polypeptide comprises at least a fragment with a structure as shown in Formula 4 or Formula 5: (L) n X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 SS-type 4; In Equation 4, L represents a leucine residue, S represents a serine residue, n is 1 or 2, and X1-X 24 The definition is the same as in Equation 1; X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 SS(K)m Equation 5; In Equation 5, K represents a lysine residue, S represents a serine residue, m is 1 or 2, and X1-X 24 The definition is the same as in Equation 1.

[0016] In one specific embodiment, the amino acid at any site of the polypeptide is a D-type amino acid or an L-type amino acid.

[0017] In one specific embodiment, the polypeptide is selected from at least one of A1)-A18): A1) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -SerD -Dab L -Ala D -Ala D -Lys D -Lys D -Ala D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A2) The amino acid composition is Lys D -Leu D -Dab D -Ser D -Leu D -Leu D -Dab D -Thr D -Leu D -Ser D -Dab D -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab D -Thr D -Leu D -Leu D -Dab D -Ala D -Leu D -Ser D -Ser D polypeptides; A3) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -AlaD -Ala D -Thr D -Leu D -Dab L -Lys D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A4) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Ala D -Dab L -Thr D -Leu D -Leu D -Dab L -Leu D -Leu D -Ser D -Ser D polypeptides; A5) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Leu D -AlaD -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A6) The amino acid composition is Lys D -Leu D -Dab D -Ser D -Leu D -Leu D -Dab D -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab D -Dab D -Lys D -Leu D -Ala D -Thr D -Leu D -Leu D -Dab D -Ala D -Leu D -Ser D -Ser D polypeptides; A7) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Dab L -Lys D -Lys D -Dab L -Leu D -Ala D -Thr D -Leu D -Leu D -DabL -Ala D -Leu D -Ser D -Ser D polypeptides; A8) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Thr D -Leu D -Ala D -Lys D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A9) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Ala D -Ala D -Thr D -Leu D -Leu D -Dab L -Leu D -Leu D -Ser D -SerD polypeptides; A10) amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Leu D -Ala D -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D polypeptides; A11) amino acid composition is Lys D -Leu D -Ser D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Thr D -Thr D -Lys D -Lys D -Thr D -Lys D -Leu D -Ser D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ser D polypeptides; A12) amino acid composition is Lys D -Leu D -Ser D -Dab L -Leu D -LeuD -Lys D -Ser D -Leu D -Thr D -Thr D -Dab L -Dab L -Thr D -Lys D -Leu D -Ser D -Lys D -Leu D -Leu D -Dab L -Ser D -Leu D -Ser D polypeptides; A13) amino acid composition is Lys D -Leu D -Ala D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ala D -Thr D -Lys D -Lys D -Thr D -Lys D -Leu D -Ala D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ser D polypeptides; A14) amino acid composition is Lys D -Leu D -Ala D -Dab L -Leu D -Leu D -Lys D -Ser D -Leu D -Ala D -Thr D -Dab L -Dab L-Thr D -Lys D -Leu D -Ala D -Lys D -Leu D -Leu D -Dab L -Ser D -Leu D -Ser D polypeptides; A15) amino acid composition is Leu D -Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A16) amino acid composition is Leu D -Leu D -Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -LysD -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A17) amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D -Lys D polypeptides; A18) amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L-Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D -Lys D -Lys D Polypeptides.

[0018] Further, the polypeptide is selected from at least one of A1), A2), A5), A7), A9), A11), and A13). Even further, the polypeptide is A1), and its amino acid sequence is SEQ ID NO:2.

[0019] It should be noted that, in this invention, when a polypeptide includes at least a fragment with the structure shown in Formula 1, it indicates that the polypeptide includes the complete fragment shown in Formula 1. Other amino acids may also be linked to the N-terminus and / or C-terminus of the polypeptide fragment shown in Formula 1. No amino acids are inserted into the complete fragment shown in Formula 1; that is, a portion of the amino acid fragment of the polypeptide molecule remains completely identical to the fragment shown in Formula 1. When a polypeptide is expressed as being composed of a defined number of amino acids, it indicates that the polypeptide does not include any other amino acids besides the defined amino acids.

[0020] In one specific embodiment, the N-terminus and / or C-terminus of the polypeptide contains protecting groups. The polypeptides of this invention possess antibacterial activity on their own, or when they are covalently coupled to or bound to other molecules. Without destroying or significantly altering the antibacterial activity, the polypeptide molecules can be modified according to methods known in the art, for example: the N-terminus can be covalently linked to various functional molecules via acylation or alkylation, and the C-terminus can be covalently linked to various functional molecules via acylation or esterification, as long as the antibacterial activity is not destroyed or substantially not destroyed.

[0021] Further, the amino-terminal protecting group is any one of acetyl, amino, maleyl, succinyl, tert-butoxycarbonyl, benzyloxy, or other hydrophobic groups or macromolecular carrier groups; the carboxyl-terminal protecting group is any one of amino, amide, carboxyl, tert-butoxycarbonyl, or other hydrophobic groups or macromolecular carrier groups. Even further, the N-terminal amino acid of the polypeptide is acetylated; and / or the C-terminal amino acid of the polypeptide is amidated.

[0022] Furthermore, the polypeptide provided by the present invention is preferably at least one of B1)-B7): B1)Ac-Lys D -Leu D-Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -To the D -To the D -Lily D -Lily D -To the D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -To the D -Leu D -Ser D -Ser D -NH2; B2)Ac-Lys D -Leu D -Dab D -Ser D -Leu D -Leu D -Dab D -Thr D -Leu D -Ser D -Dab D -To the D -Lily D -To the D -To the D -Lily D -Leu D -Dab D -Thr D -Leu D -Leu D -Dab D -To the D -Leu D -Ser D -Ser D -NH2; B3)Ac-Lys D -Leu D -Dab L -Ser D -Leu D -Leu D-Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Leu D -Ala D -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D -NH2; B4)Ac-Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Dab L -Lys D -Lys D -Dab L -Leu D -Ala D -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D -NH2; B5)Ac-Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D-No D -No D -Lys D -Dab L -Dab L -Lys D -No D -No D -Thr D -Leo D -Leo D -Dab L -Leo D -Leo D -Ser D -Ser D -NH2; B6)Ac-Lys D -Leo D -Ser D -Lys D -Leo D -Leo D -Lys D -Ser D -Leo D -Thr D -Thr D -Lys D -Lys D -Thr D -Lys D -Leo D -Ser D -Lys D -Leo D -Leo D -Lys D -Ser D -Leo D -Ser D -NH2; B7)Ac-Lys D -Leo D -No D -Lys D -Leo D -Leo D -Lys D -Ser D -Leo D -No D -Thr D -Lys D -Lys D -Thr D -Lys D -Leo D-Ala D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ser D -NH2; In the polypeptides shown in B1)-B7), Ac represents acetyl group and NH2 represents amide group.

[0023] In this invention, the pharmaceutical salt of the polypeptide refers to the salt formed by the polypeptide represented by Formula 1 and a pharmaceutically acceptable acid or base. The term "pharmaceutical salt" refers to a substance suitable for human use without excessive adverse reactions or side effects. Specifically, the medicinal salts include acetates, trifluoroacetates, lacturonates, benzenesulfonates, benzoates, malates, bicarbonates, maleates, bisulfates, mandelates, tartrates, methanesulfonates, borates, bromides, methyl sulfates, mucilages, carbonates, naphthalenesulfonates, chlorides, nitrates, citrates, citrates, ammonium salts, dihydrochlorides, oleates, ethylenediaminetetraacetate, oxalates, ethylenedisulfonates, palmitates, pantothenates, fumarates, phosphates / bisphosphates, glucono-p-phosphates, polygalacturonates, gluconates, salicylates, glutamates, stearates, sulfates, hydroxybenzoates, basic acetates, succinates, hydrobromicates, tannins, hydrochlorides, tartrates, hydroxynaphthylates, 8-chlorotheophylline salts, iodides, toluenesulfonates, valerates, etc. Depending on their intended use, pharmaceutical salts can be formed from cations such as sodium, potassium, aluminum, calcium, lithium, manganese, zinc, and bismuth, or from bases such as ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxylate. These salts can be prepared using standard methods, such as by reacting free acids with organic or inorganic bases. In the presence of a basic group such as an amino group, acidic salts such as hydrochlorides, hydrobromines, acetates, trifluoroacetates, and primates can be used as dosage forms; in the presence of an acidic group (such as -COOH) or an alcohol group, pharmaceutically acceptable esters such as acetates, maleates, and chloromethyl trimethylacetate, as well as esters known in the literature for improving solubility and hydrolysis, can be used as sustained-release and prodrug formulations.

[0024] In this invention, the enantiomer of a polypeptide refers to a polypeptide whose amino acid configuration is completely opposite to that of the polypeptide, for example, a polypeptide with an amino acid composition of Lys D -Leu D -Dab D -Ser D -Leu D-Leu D -Dab D -Thr D -Leu D -Ser D -Dab D -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab D -Thr D -Leu D -Leu D -Dab D -Ala D -Leu D -Ser D -Ser D The polypeptide and amino acid composition is Lys L -Leu L -Dab L -Ser L -Leu L -Leu L -Dab L -Thr L -Leu L -Ser L -Dab L -Ala L -Lys L -Ala L -Ala L -Lys L -Leu L -Dab L -Thr L -Leu L -Leu L -Dab L -Ala L -Leu L -Ser L -Ser L The polypeptides are enantiomers.

[0025] In a second aspect, the present invention provides a composition comprising any of the polypeptides described above, their pharmaceutical salts, or their enantiomers.

[0026] The compositions provided by this invention can be pharmaceutical compositions, which, in addition to including any of the polypeptides, their pharmaceutical salts, or their enantiomers described above, also include a pharmaceutically acceptable carrier. Further, the pharmaceutically acceptable carrier includes at least one of the following: excipients, lubricants, pH adjusters, stabilizers, encapsulating agents, sprays, binders, fillers, disintegrants, humectants, transdermal absorbents, absorption enhancers, surfactants, flavoring agents, colorants, preservatives, sweeteners, osmotic pressure regulators, and adsorbents.

[0027] The pharmaceutical composition provided by the present invention uses any of the above-described polypeptides, their pharmaceutical salts, or their enantiomers as the main active ingredients. It is understood that it may also include other antibacterial active ingredients.

[0028] The dosage form of the pharmaceutical composition provided by this invention can be determined according to actual needs, and can be selected from, for example, injections, tablets, capsules, lozenges, oral liquids, granules, powders, pills, powders, ointments, syrups, mixtures, elixirs, effervescent tablets, pastes, emulsions, teas, pills, suspensions, powders, implants, ointments, creams, gels, plasters, creams, sprays, drops, patches, films, and lotions. Further, the dosage form of the drug is selected from injections, tablets, capsules, granules, oral liquids, ointments, creams, gels, eye drops, sprays, patches, films, and lotions.

[0029] Furthermore, commonly used excipients for injectable preparations include at least one of disodium EDTA, Tween 80, mannitol, glycerin, and propylene glycol. Commonly used excipients for oral solid dosage forms include microcrystalline cellulose, low-substituted hydroxypropyl cellulose, polyvinylpyrrolidone, microcrystalline silica, starch, dextrin, sucrose, lactose, talc, magnesium stearate, sodium carboxymethyl starch, croscarmellose, and pregelatinized starch. Commonly used excipients for topical preparations include mannitol, polysorbate-80, polyethylene glycol, polyoxyethylene stearate, glycerin, carbomer, triethanolamine, ethanol, polyvinylpyrrolidone, tartaric acid, sodium bicarbonate, polyvinyl alcohol, sodium benzoate, microcrystalline cellulose, and hydroxypropyl methylcellulose. Excipients for oral liquid preparations include ethanol, ethylparaben, methylparaben, polysorbate-80, sodium benzoate, sorbic acid, honey, sucrose, sodium bisulfite, sodium thiosulfate, ascorbic acid, thiourea, disodium EDTA, phosphoric acid, citric acid, glycerol, lactose, etc.

[0030] The dosage range of the pharmaceutical composition provided by the present invention is 0.01-500 mg by weight. Further, the dosage range of the polypeptide in the pharmaceutical composition is: 0.1-50 mg / kg for injections; 1 / 10000-10% / vial for topical applications; 0.1-50 mg / kg for oral applications; 1 / 10000-10% / vial for eye drops; 1 / 100000-1‰ / vial for lotions; and 1 / 10000-10% / vial for inhalers.

[0031] The composition provided by the present invention can also be an antibacterial agent, which is mainly an external agent and can be used in fields such as medical and health care, personal care products or environmental disinfection.

[0032] Thirdly, the present invention provides the use of any of the above-described polypeptides, their pharmaceutical salts, their enantiomers, or the above-described compositions, wherein the use is selected from at least one of B1)-B3): B1) Use in the preparation of products for the prevention and / or mitigation and / or treatment of microbial infections; B2) Application in the prevention and / or restriction and / or elimination of microbial growth; B3) Application in the preparation of products for preventing and / or limiting and / or eliminating the growth of microorganisms.

[0033] The microorganisms provided by this invention include bacteria, viruses, fungi, or protozoa, and microbial infections are caused by one or more pathogens of the aforementioned microorganisms. For example, infections caused simultaneously by two different bacteria.

[0034] Fourthly, the present invention provides a method for preventing and / or limiting and / or eliminating microbial growth for non-disease treatment purposes, comprising: contacting any of the above-described polypeptides, their pharmaceutical salts, or their enantiomers or the above-described compositions with a sample to be treated to prevent and / or limit and / or eliminate the growth of microorganisms in the sample to be treated.

[0035] The samples to be processed provided by this invention are mainly environmental samples and do not involve disease prevention and treatment.

[0036] Fifthly, the present invention provides a method for preventing and / or alleviating and / or treating microbial infections in a subject, comprising administering a therapeutically effective amount of any of the above-described polypeptides, their pharmaceutical salts, their enantiomers, or the above-described compositions to the subject.

[0037] The subjects provided in this invention can be mammals. Mammals can be selected from bovines, equines, felines, canines, lagos, suidae, camels, rodents, and primates, including but not limited to cattle, horses, goats, sheep, cats, rabbits, pigs, camels, alpacas, rats, mice, guinea pigs, non-human primates (such as apes, monkeys, baboons, and orangutans), and humans, preferably cattle, horses, dogs, goats, sheep, pigs, camels, rats, mice, monkeys, and humans.

[0038] In this invention, "therapeutic effective amount" refers to the amount of a pharmaceutically acceptable carrier, formulation, composition, or reagent, or a physiologically acceptable salt of an active compound; that is, a sufficient dose to improve the adverse condition of a treated patient, animal, substance, or object. "Improvement" means, during treatment, a reduction or alleviation of the negative effects of the condition or a reduction in infection.

[0039] In this invention, the "therapeutic effective dose" is variable and ultimately determined by the attending physician, depending on the method and route of administration, the individual's age and / or weight, and the individual's condition. The dose administered to an individual, in the context of this invention, should be sufficient over a period of time to elicit a beneficial response in the individual.

[0040] The polypeptides, their pharmaceutical salts, or their enantiomers or compositions provided by this invention can be prepared as any medically usable biological carrier or formulation for administration to subjects infected with microorganisms.

[0041] The polypeptides provided by this invention have excellent antibacterial activity and low toxicity, and can be applied to various stubborn infectious diseases and common infections, serving as excellent alternatives or adjuvant drugs to existing antibiotics. Attached Figure Description

[0042] Figure 1 The diagram shows the helical wheel and helical network of polypeptide SQ-1; where 1A is the helical wheel of polypeptide SQ-1, 1B is the helical network of polypeptide SQ-1, DAB represents D-type 2,4-diaminobutyric acid, and hydrophobic amino acids are marked with yellow squares. Figure 2 The diagram shows the helical rings and helical network diagrams of polypeptide SQ-2; where 1A is the helical ring of polypeptide SQ-2, 1B is the helical network diagram of polypeptide SQ-2, Dab represents L-type 2,4-diaminobutyric acid, and hydrophobic amino acids are marked with yellow squares. Detailed Implementation

[0043] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, embodiments of this invention, and should not be construed as limiting the invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention. In the description of this invention, it should be understood that the terminology used is for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0044] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0045] Terminology Definitions and Explanations In general, the terms and phrases used herein have their recognized meanings in the art, which can be found by referencing standard textbooks, journal articles, and knowledge known to those skilled in the art. The following definitions are provided to clarify their specific application in this invention.

[0046] As used herein, the term "amino acid" refers to any natural or non-natural amino acid, whether naturally occurring or synthetically produced, including both L- and D-type amino acids. The term also includes amino acid analogs used in peptide analogs or peptide-like compounds. Furthermore, the term includes modified, non-natural amino acids or synthetic amino acid derivatives, such as diaminobutyric acid (GABA) and diaminopropionic acid (DAP).

[0047] The antimicrobial peptides of this invention are composed of amino acids linked by peptide bonds. Under hydrophobic conditions, the antimicrobial peptides generally exhibit an α-helical conformation. The sequence of the antimicrobial peptides is generally from the amino terminus to the carboxyl terminus, i.e., from the N-terminus to the C-terminus. Unless otherwise specified, the amino acids are L-type amino acids; when the polypeptide is composed entirely of L-type amino acids, it is called an L-enantiomer. When the polypeptide is composed entirely of D-type amino acids, it is called a D-enantiomer.

[0048] The term “minimum inhibitory concentration” (MIC) refers to the minimum concentration of an antimicrobial agent (e.g., an antimicrobial peptide) required to inhibit bacterial growth or otherwise alter its physiological function under certain conditions (e.g., in a liquid culture medium). The minimum inhibitory concentration for different bacteria can be determined using standard techniques of numerical values ​​in the art.

[0049] The term "minimum hemolytic concentration" (MHC) refers to the lowest concentration of an antimicrobial drug or antimicrobial peptide required to cause hemolysis of blood cells under certain conditions. MHC can be measured using red blood cells (RBCs) from different species, including human red blood cells (hRBCs), as well as red blood cells from rodents and molars.

[0050] The term "therapeutic index" (TI) refers to the ratio of the lowest hemolytic concentration (MHC) of an antimicrobial drug to the lowest inhibitory concentration (MIC). A higher TI value indicates higher antimicrobial specificity.

[0051] The term "microorganism" broadly refers to bacteria, fungi, viruses, and protozoa. Specifically, the term can refer to microorganisms that have a lipid bilayer structure or structural components. In a particular embodiment, the membrane is a cell membrane. It typically includes pathogens, fungi, viruses, and protozoa known in the art. Bacteria include Gram-positive and Gram-negative bacteria, as well as families of soft-membrane bacteria such as Mycoplasma (…). Mycoplasma ) and acholestapeptides ( Acholeplasma The types of Gram-positive bacteria that may be susceptible include, but are not limited to, *Escherichia coli*. Escherichia coli ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa Salmonella typhimurium ( Salmonella Haemophilus () Hemophilus influenza ), Neisseria ( Neisseria ), Vibrio cholerae ( Vibrio cholerae Vibrio parahaemolyticus Vibrio parahaemolyticus ) and Helicobacter pylori ( Helicobacter pylori Examples of potentially susceptible Gram-positive bacteria include, but are not limited to, Staphylococcus aureus. Staphylococcus aureus Staphylococcus epidermidis () Staphylococcus epidermis ), agalactococcus ( Staphylococcus agalactiae Group A Streptococcus, Streptococcus pyogenes ( Streptococcus pyogenes ), Enterococcus faecalis ( Enterococcus faecalis Group B Gram-positive streptococci, dried corynebacteria ( Corynebacterium xerosis ) and Listeria monocytogenes ( Listeria monocytogenes Examples of potentially susceptible fungi include yeasts such as Candida albicans. Candida albicans Examples of potentially susceptible viruses include measles virus, herpes simplex virus (HSV-1 and HSV-2), members of the herpes family (HIV), hepatitis C virus, varicella-zoster virus, sheep demyelination virus, and cytomegalovirus. Susceptible protozoa include Giardia (…). Giardia ).

[0052] The names of the amino acids and their corresponding abbreviations involved in the following examples are shown in Table 1: Table 1. Abbreviations and names of the amino acids involved in this invention.

[0053] Example 1, Polypeptide The polypeptide provided by this invention is based on the amino acid composition Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D The peptide was derived from an antimicrobial peptide (reference: Journal of Medicinal Chemistry 2019, 62, 3354-3366, code D102), and the amino acid composition of the peptide is shown in Table 2.

[0054] The polypeptide SQ-1 is composed of 26 amino acid residues with the sequence Ac-Lys. D -Leu D -Dab D -Ser D -Leu D -Leu D -Dab D -Thr D -Leu D -Ser D -Dab D -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -DabD -Thr D -Leu D -Leu D -Dab D -Ala D -Leu D -Ser D -Ser D -NH2, such as Figure 1 As shown, polypeptide SQ-1 is an amphiphilic α-helical antimicrobial peptide with one polar surface and one nonpolar surface, as illustrated in the helical diagram ( Figure 1 In diagram 1A, hydrophilic surfaces are represented by hollow arcs, and hydrophobic surfaces are represented by solid arcs. In the spiral mesh diagram ( Figure 1 In section 1B), hydrophobic amino acids are represented by yellow squares. Ac indicates N-terminal acetylation, and NH2 indicates C-terminal amidation. The polar surface of the SQ-1 polypeptide consists of 12 hydrophilic amino acids (5 Dab, 4 Ser, 2 Thr, and 1 Lys) and 3 hydrophobic amino acids (2 Ala and 1 Leu). In contrast, its nonpolar surface contains 9 hydrophobic amino acids (7 Leu and 2 Ala) and 2 hydrophilic amino acids (2 Lys).

[0055] Polypeptide SQ-1 is composed of D-type amino acids. This embodiment also provides its enantiomer (named polypeptide SQ-1L), whose amino acid composition is Ac-Lys. L -Leu L -Dab L -Ser L -Leu L -Leu L -Dab L -Thr L -Leu L -Ser L -Dab L -Ala L -Lys L -Ala L -Ala L -Lys L -Leu L -Dab L -Thr L -Leu L -Leu L -Dab L -Ala L -Leu L -Ser L -Ser L-NH2 is mainly composed of the corresponding L-amino acids. Therefore, SQ-1L is stereochemically completely opposite to the corresponding SQ-1. Numerous studies have shown that enantiomeric peptides are consistent in various physicochemical properties and biological activities; therefore, in the examples below, only experimental data of some representative peptide sequences are presented.

[0056] The helical wheel diagram and helical network diagram of peptide SQ-2 are as follows: Figure 2 As shown.

[0057] Table 2. Amino acid composition of the polypeptides provided in the embodiments of the present invention.

[0058] In Table 2, unless otherwise specified by footnote, a. are all D-type enantiomers. The subscript L after an amino acid indicates that the amino acid is an L-type amino acid; X represents the amino acid Dab. The polypeptides shown in SQ-1 to SQ-17 correspond to the polypeptides shown in SEQ ID NO:1-19 in the sequence listing, respectively. The N-terminus of all polypeptides shown in SQ-1 to SQ-17 in Table 2 is protected with an acetyl group, and the C-terminus is protected with an amide group.

[0059] Example 2: Antibacterial drug susceptibility test (MIC) of the polypeptide provided by the present invention. 2.1 Test strains: There are 3 standard strains: Staphylococcus aureus (ATCC25923), Escherichia coli (ATCC25922) and Pseudomonas aeruginosa (ATCC27853).

[0060] 2.2 Experimental Methods: After resuscitation and activation, third-generation strains of each bacterial strain were placed in liquid culture medium and cultured for several hours. The bacterial counts were then performed under a microscope using a counting chamber. The bacterial suspension concentration was adjusted to 1×10⁻⁶ using MH broth medium. 6 CFU / mL, ready for use. Using a micropipette, add 100 μL of MH broth medium to each well of a sterile U-shaped 96-well plate. Add 100 μL of the prepared peptide solution to the first well, mix thoroughly, then add 100 μL from the first well to the second well. Repeat this serial dilution process until the 10th well is reached. After mixing, discard the excess 100 μL of solution. Add 1.0 × 10⁻⁶ CFU / mL to wells 1-11. 6 100 μL of bacterial culture (cfu / mL) was added to well 12 as a blank control. The plate was gently shaken for 2 min and incubated at 37℃ for 18 h. The lowest drug concentration in the wells where no aseptic growth was observed was defined as the MIC. All drugs were tested in triplicate. The MIC range for the target peptide was set at 32 μg / mL–0.0625 μg / mL (final concentration). The final bacterial concentration was 5 × 10⁻⁶.5 cfu / mL.

[0061] 2.3 Experimental Results: The antibacterial effects of representative peptide samples of the SQ-1 series and their control drug D102 on the three bacterial strains are shown in Table 3.

[0062] Table 3. Minimum inhibitory concentrations (μg / mL) of some peptides provided in the embodiments of the present invention against three microorganisms.

[0063] As shown in Table 3, compared with the antibacterial activity of D102, the peptides provided by this invention have a stronger bactericidal effect. In particular, the overall bactericidal effect of this series of antimicrobial peptides is stronger against Gram-negative bacteria Escherichia coli ATCC25922, showing stronger bactericidal specificity.

[0064] Example 3: Hemolysis test of the polypeptide provided by the present invention According to the hemolysis and agglutination test method in Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China, the hemolytic reaction of compounds to rabbits was compared and analyzed using an in vitro tube method (visual observation method). The experimental results are shown in Table 4.

[0065] Table 4. Hemolytic values ​​(MHC) of polypeptides in rabbit blood.

[0066] Example 4: Therapeutic index of the polypeptide provided by the present invention To better evaluate the biological activity of peptides, the therapeutic index (TI), a widely used parameter representing the specificity of antimicrobial drugs, was used for comparison. The therapeutic index is calculated from the ratio of MHC (hemolytic activity) to MIC (antimicrobial activity) (TI = MHC / MIC); the higher the value, the stronger the antimicrobial specificity of the peptide. The results are shown in Table 5.

[0067] Table 5. Therapeutic Index (TI) of Peptides

[0068] As shown in Table 5, the therapeutic index of the polypeptide provided by the present invention is significantly larger than that of D102. In particular, the therapeutic index of Escherichia coli ATCC25922 is significantly increased compared to that of D102, which means that the antibacterial specificity is significantly increased.

[0069] Example 5: Toxicity test of the polypeptide SQ-2 provided by the present invention ICR mice were randomly divided into groups of 10 mice each, with an equal number of males and females, and the weight difference between animals in the same group and during the same experiment should not exceed 4 g. Mice in each group were marked with a 5% picric acid solution. The doses that caused 0% (Dn) and 100% (Dm) mortality in animals were determined through preliminary experiments, and five dose groups were established within this range with a suitable group interval (0.8-0.9). Different doses of the test drug were administered via tail vein injection at a dosage volume of 10 mL / kg. Mice were fasted for 16 hours before administration and observed continuously for 14 days after administration. Behavioral status, toxic reactions, and mortality were observed and recorded, and the results were calculated according to the formula: The LD50 was calculated.

[0070] Table 6. Survival status of animals 14 days after a single intravenous administration of SQ-2

[0071] The LD value of peptide SQ-2 was calculated using the probability unit weighted regression method (Bliss method) in SPSS software. 50 It is 16.515 mg / kg.

[0072] As can be seen from the above embodiments, the polypeptide provided by the present invention has excellent antibacterial activity and low toxicity, and can be applied to various stubborn infectious diseases and common infections, serving as an excellent alternative or adjuvant drug to existing antibiotics.

[0073] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A polypeptide, or a pharmaceutical salt thereof, or an enantiomer thereof, characterized in that, The polypeptide includes at least a fragment with the structure shown in Formula 1: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 Equation 1; In Equation 1, X1 is selected from one of Lys, Dab, Ala, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X2 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X3 is selected from one of Dab, Ser, Ala, Lys, Thr, and Leu; X4 is selected from one of Ser, Lys, Dab, Thr, Ala, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X5 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X6 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X7 is selected from one of Dab, Lys, Ser, Ala, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X8 is selected from Thr, Ser, and Ala; X9 is selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X 10 Selected from one of Ser, Thr, Ala, Dab, Lys, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 11 Selected from one of Dab, Ala, Thr, Ser, Lys, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 12 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 13 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 14 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 15 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 16 Selected from one of Ala, Lys, Dab, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 17 Selected from one of Leu, Ala, Ser, Trp, Phe, Ile, Val, Nle, Nva, Dab, Lys, Thr; X 18 Selected from one of Dab, Ala, Lys, Ser, Thr, Leu, Trp, Phe, Ile, Val, Nle, and Nva; X 19 Selected from one of Thr, Lys, Leu, Dab, Ala, Ser, Trp, Phe, Ile, Val, Nle, and Nva; X 20 Selected from one of Leu, Ala, Trp, Phe, Ile, Val, Nle, and Nva; X 21 Selected from one of Leu, Lys, Dab, Ala, Trp, Phe, Ile, Val, Nle, Nva, Ser, Thr; X 22 Selected from one of Dab, Ser, Ala, Lys, Thr, and Leu; X 23 Selected from one of Ala, Leu, Dab, Ser, Lys, Thr, Trp, Phe, Ile, Val, Nle, and Nva; X 24 Selected from one of Leu, Ser, Ala, Trp, Phe, Ile, Val, Nle, Nva, Thr; When the amino acid composition of the polypeptide is Lys-Leu-Dab-Ser-Leu-Leu-Dab-Thr-Leu-Ser-Dab-Ala-Lys-Ala-Ala-Lys-Leu-Dab-Thr-Leu-Leu-Dab-Ala-Leu, the amino acids Dab at positions 3, 7, 11, and 22 are all of type D.

2. The polypeptide, or its pharmaceutical salt, or its enantiomer, according to claim 1, characterized in that, The polypeptide includes at least a fragment with the structure shown in Formula 2: KLX3X4LLX7X8LX 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 LX 21 X 22 X 23 X 24 Formula 2; In Equation 2, K represents a lysine residue, L represents a leucine residue, and the rest of the definitions are the same as in Equation 1.

3. The polypeptide, or its pharmaceutical salt, or its enantiomer, according to claim 1 or 2, characterized in that, The polypeptide includes at least a fragment with the structure shown in Formula 3: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 SS type 3; In Equation 3, S represents a serine residue, X1-X 24 The definition is the same as in Equation 1.

4. The polypeptide, or its pharmaceutical salt, or its enantiomer, according to any one of claims 1-3, characterized in that, The polypeptide comprises at least a fragment with a structure as shown in Formula 4 or Formula 5: (L) n X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 SS type 4; In Equation 4, L represents a leucine residue, S represents a serine residue, n is 1 or 2, and X1-X 24 The definition is the same as in Equation 1; X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 SS(K)m formula 5; In Equation 5, K represents a lysine residue, S represents a serine residue, m is 1 or 2, and X1-X 24 The definition is the same as in Equation 1.

5. The polypeptide, or its pharmaceutical salt, or its enantiomer, according to any one of claims 1-4, characterized in that, The amino acid at any site of the polypeptide is a D-type amino acid or an L-type amino acid.

6. The polypeptide, or its pharmaceutical salt, or its enantiomer, according to any one of claims 1-5, characterized in that, The polypeptide is selected from at least one of A1)-A18): A1) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Ala D -Lys D -Lys D -Ala D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A2) The amino acid composition is Lys D -Leu D -Dab D -Ser D -Leu D -Leu D -Dab D -Thr D -Leu D -Ser D -Dab D -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab D -Thr D -Leu D -Leu D -Dab D -Ala D -Leu D -Ser D -Ser D polypeptides; A3) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Thr D -Leu D -Dab L -Lys D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A4) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Ala D -Dab L -Thr D -Leu D -Leu D -Dab L -Leu D -Leu D -Ser D -Ser D polypeptides; A5) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Leu D -Ala D -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A6) The amino acid composition is Lys D -Leu D -Dab D -Ser D -Leu D -Leu D -Dab D -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab D -Dab D -Lys D -Leu D -Ala D -Thr D -Leu D -Leu D -Dab D -Ala D -Leu D -Ser D -Ser D polypeptides; A7) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Dab L -Lys D -Lys D -Dab L -Leu D -Ala D -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A8) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Thr D -Leu D -Ala D -Lys D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A9) The amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Ala D -Ala D -Thr D -Leu D -Leu D -Dab L -Leu D -Leu D -Ser D -Ser D polypeptides; A10) amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Ala D -Ala D -Lys D -Dab L -Dab L -Lys D -Leu D -Ala D -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D polypeptides; A11) amino acid composition is Lys D -Leu D -Ser D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Thr D -Thr D -Lys D -Lys D -Thr D -Lys D -Leu D -Ser D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ser D polypeptides; A12) amino acid composition is Lys D -Leu D -Ser D -Dab L -Leu D -Leu D -Lys D -Ser D -Leu D -Thr D -Thr D -Dab L -Dab L -Thr D -Lys D -Leu D -Ser D -Lys D -Leu D -Leu D -Dab L -Ser D -Leu D -Ser D polypeptides; A13) amino acid composition is Lys D -Leu D -Ala D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ala D -Thr D -Lys D -Lys D -Thr D -Lys D -Leu D -Ala D -Lys D -Leu D -Leu D -Lys D -Ser D -Leu D -Ser D polypeptides; A14) amino acid composition is Lys D -Leu D -Ala D -Dab L -Leu D -Leu D -Lys D -Ser D -Leu D -Ala D -Thr D -Dab L -Dab L -Thr D -Lys D -Leu D -Ala D -Lys D -Leu D -Leu D -Dab L -Ser D -Leu D -Ser D polypeptides; A15) amino acid composition is Leu D -Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A16) amino acid composition is Leu D -Leu D -Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D polypeptides; A17) amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D -Lys D polypeptides; A18) amino acid composition is Lys D -Leu D -Dab L -Ser D -Leu D -Leu D -Dab L -Thr D -Leu D -Ser D -Dab L -Ala D -Lys D -Ala D -Ala D -Lys D -Leu D -Dab L -Thr D -Leu D -Leu D -Dab L -Ala D -Leu D -Ser D -Ser D -Lys D -Lys D Polypeptides.

7. The polypeptide, or its pharmaceutical salt, or its enantiomer, according to any one of claims 1-6, characterized in that, The N-terminus and / or C-terminus of the polypeptide also include protecting groups.

8. A composition, characterized in that, Includes the polypeptide, pharmaceutical salt thereof, or enantiomer thereof as described in any one of claims 1-7.

9. The use of the polypeptide according to any one of claims 1-7, or a pharmaceutical salt thereof, or an enantiomer thereof, or the composition according to claim 8, characterized in that, The application is selected from at least one of B1)-B3): B1) Use in the preparation of products for the prevention and / or mitigation and / or treatment of microbial infections; B2) Application in the prevention and / or restriction and / or elimination of microbial growth; B3) Application in the preparation of products for preventing and / or limiting and / or eliminating the growth of microorganisms.

10. A method for preventing and / or limiting and / or eliminating microbial growth for purposes other than disease treatment, characterized in that, include: Contacting the polypeptide, pharmaceutical salt thereof, or enantiomer thereof, or composition thereof according to any one of claims 1-7 with the sample to be treated, to prevent and / or limit and / or eliminate the growth of microorganisms in the sample to be treated.

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