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Melittin and flexible polyethylene glycol based antibacterial drug

An antibacterial drug, polyethylene glycol technology, applied in the field of biomedicine, can solve the problems of reducing clearance or plasma protein adsorption, weakening the biological activity of modified molecules, etc.

Active Publication Date: 2020-11-06
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the high hydration structural characteristics of polyethylene glycol (PEG) molecules, PEG modification of drug molecules has been widely used in clinical medicine and scientific research, however, it is mainly used to improve the dispersion of drug molecules in aqueous solution At the same time, the masking effect of PEG on drug molecules can reduce the drug's in vivo clearance or plasma protein adsorption, reduce the inflammatory response or immunogenic response and improve the drug's cytocompatibility, but unfortunately, PEG modification Will more or less weaken the biological activity of the modified molecule

Method used

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  • Melittin and flexible polyethylene glycol based antibacterial drug
  • Melittin and flexible polyethylene glycol based antibacterial drug
  • Melittin and flexible polyethylene glycol based antibacterial drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: antibacterial effect and cytotoxicity test: PEG 12K Preparation of -1*Mel Complex and Improvement of Antibacterial Properties

[0054] We pre-designed PEG molecules with different structures and molecular weights, which have active sites that can interact with amino groups of polypeptides (such as unnatural organic group maleimide). The active site of Mel and PEG is chemically coupled to obtain PEGw-m*Mel complexes with different structures (here, w is the molecular weight of PEG, m is the number of polypeptides in each complex, see figure 1 ). in PEG 12K - 1*Mel as an example, wherein each Mel peptide is end-bonded with a single-chain PEG molecule (average molecular weight 12000). Characterizations such as dynamic light scattering (DLS), UV-Vis absorption spectrum, and SDS-polyacrylamide gel electrophoresis all confirmed that PEG molecules were successfully modified on Mel ( figure 2 ).

[0055] We first PEG 12k The -1*Mel complex was applied to li...

Embodiment 2

[0059] Example 2: Mechanism study of enhanced antibacterial activity: PEG 12K Kinetic interactions of -1*Mel complexes with membranes

[0060] Antimicrobial peptide-induced physical permeability (such as perforation) of bacterial membranes is considered to be the main molecular mechanism for the antibacterial ability of AMPs by Mel et al. Our SEM images of the bacteria also showed severe disruption of the bacterial membrane due to drug exposure. To monitor the dynamic interaction between the drug and the cell membrane in real time, we performed a GUV leakage kinetic test. Figure 6 The first image in shows a typical GUV consisting of DOPC labeled with 1 mol% red fluorescent Rh-PE encapsulated with green fluorescent calcein. Calcein is a water-soluble, membrane-impermeable fluorophore and is therefore commonly used to test membrane permeability. Under confocal microscopy, this calcein-encapsulated GUVs showed no calcein leakage for more than 4 hours. Addition of native Mel ...

Embodiment 3

[0065] Example 3: The influence of molecular structure on the bactericidal function of the compound

[0066] From a "biophysical" point of view, structure determines the function of biological macromolecules. As mentioned above, a series of PEG-Mel complexes with different structures were constructed by decorating Mel with PEG. Three complex structures were designed ( figure 1 ), including linear structures (i.e., each Mel end is linked to a single-chain PEG), cross-structures (i.e., two or four Mel molecules conjugated to a two-armed or four-armed PEG), and multi-branched structures (in which multiple polypeptides modified on the PEG backbone). PEGs of different molecular weights are also composed of flexible long chains (M W >=5K) or rigid short chains (Mw<=200).

[0067] Table 1. Comparison of biological activities of natural Mel and PEG-Mel complexes with different molecular structures

[0068]

[0069] PEG W -m*Mel complexes were applied to live cells to test the...

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Abstract

The invention discloses a melittin and flexible polyethylene glycol based antibacterial drug, and belongs to the technical field of biological medicine. Flexible polyethylene glycol is adopted to perform covalent modification on melittin so as to construct an antibacterial compound molecule having a special design structure. Compared with original melittin, molecular modification strengthens the self-assembling capability of a compound, so that a larger aggregate can be formed; the compact aggregate shows lipid-specific binding behaviors so as to target bacteria without damaging mammalian cells; and during the subsequent membrane effect, the melittin parts in the compound aggregate can form polypeptide channels in membranes, so that the polyethylene glycol parts can be promoted to successfully pass through the membranes and finally form stable transmembrane pores. Thus, compared with the original melittin, antibacterial efficiency can be enhanced, and side effects and toxicity can be reduced as well.

Description

[0001] This application is the application number: 202010129914.3, the application date is: February 28, 2020, and the application name is: a divisional application for an antibacterial drug based on antibacterial peptide and hydrophilic polymer and its preparation method technical field [0002] The invention relates to an antibacterial drug based on melittin and flexible polyethylene glycol, belonging to the technical field of biomedicine. Background technique [0003] Bacterial resistance to traditional antibiotics is a serious threat to human health around the world. Therefore, we urgently need to develop a new class of antibacterial drugs that are not prone to drug resistance. Antimicrobial peptides (AMPs) are naturally occurring peptides with broad-spectrum antibacterial functions. Different from the antibacterial mechanism of traditional antibiotics, antimicrobial peptides directly kill bacteria by destroying the bacterial cell membrane and causing the leakage of the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K38/17A61P31/04
CPCA61K47/60A61K38/1767A61P31/04Y02A50/30
Inventor 元冰窦玉江杨恺刘娇娇
Owner SUZHOU UNIV
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