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Antibacterial drug based on antimicrobial peptide C-terminal connection

A technology of antibacterial drugs and antibacterial peptides, applied in the field of antibacterial drugs

Active Publication Date: 2020-09-22
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disadvantages of this method: After all, nanoparticles have biological toxicity that cannot be ignored, especially heavy metal particles such as gold and silver.
However, the antibacterial activity of antimicrobial peptides needs to be further improved

Method used

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  • Antibacterial drug based on antimicrobial peptide C-terminal connection
  • Antibacterial drug based on antimicrobial peptide C-terminal connection
  • Antibacterial drug based on antimicrobial peptide C-terminal connection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Design of polypeptide machinery by PEG modification

[0033]First of all, this embodiment designs Mel with single arm (a PEG short chain is connected to the C-terminus of one Mel, P-Mel) and double arms (a PEG chain twice as long is connected to the C-terminus of two Mel, D-Mel). Connectors, and simulate the situation of two kinds of connectors and native Mel forming pores on the membrane. Compared with the original type Mel at the concentration of H / L=1 / 43 to form pores (the probability of forming pores is 33%, figure 1 B), both P-Mel and D-Mel can form pores at this concentration (the probability of forming pores is 100%). In addition, native Mel forms transient pores in the membrane, while P-Mel and D-Mel form very stable pores in the membrane (the polypeptide forms a transmembrane state in the membrane). These results indicated that the pore-forming ability of Mel was significantly improved after PEGylation. And compared with the polypeptide modified a...

Embodiment 2

[0037] This embodiment designs a series of tetrameric polypeptide machines, including star shape (S-Mel), comb shape (C-Mel), tree shape (T-Mel) and ring shape (R-Mel), such as figure 1 a. Among them, S-Mel exhibits the strongest pore-forming ability, and it can form pores at an extremely low concentration (1 / 256).

[0038] In order to understand the specific process of S-Mel pore formation, calculate the Z component of the distance between the N end of each Mel and the membrane centroid (such as image 3 ). At the beginning, all four Mels in S-Mel were adsorbed on the membrane surface, and two Mels were slightly embedded between the head and tail of the leaf phospholipids on the membrane. The two Mels then rapidly insert into the lower leaflet of the membrane to form a transmembrane channel. By analyzing the radius of gyration of S-Mel molecules, we found that S-Mel shrinks rapidly with time, and all the Mel helices gather together before forming holes. Results at lower c...

Embodiment 3

[0042] In addition to geometry and length, other properties of PEG chains can also affect the pore-forming efficiency of S-Mel, such as stiffness, which is most likely to be regulated by external stimuli (such as light, changes in solvents, or changes in salt concentration, etc.) of. A S-Mel with enhanced chain rigidity (referred to as S*-Mel) was designed, and its pore-forming efficiency was simulated at the same concentration (1 / 128). Such as Figure 4 , the results show that when the PEG chain is very rigid, the linker has been adsorbed on the membrane surface and presents a spread state, however, when the PEG chain becomes flexible again, the helix inside the linker quickly gathers and forms a transmembrane hole . The response of S-Mel to the rigidity and flexibility of PEG chains endows it with the potential for application in different cellular environments. By adjusting the stiffness of the PEG chains, the pore-forming efficiency of the complex can be effectively adj...

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Abstract

The invention discloses an antibacterial drug based on antimicrobial peptide C-terminal connection. The antibacterial drug disclosed by the invention has extremely strong membrane rupture and pore-forming ability, and a polypeptide connector S-Mel with a four-arm star-shaped structure shows the highest pore-forming efficiency. A single S-Mel molecule is enough to punch a hole at extremely low concentration, and a plurality of molecules can cooperate to form a larger hole. In addition, the S-Mel has the capability of attacking cell membranes in a specific environment and controlling the pore size. The research of designing an efficient and controllable polypeptide molecular machine is helpful for understanding the molecular mechanism of the interaction between polypeptide and a membrane, and meanwhile, an effective strategy is provided for developing the research of killing specific cells (such as bacteria and tumors) in a targeting manner.

Description

technical field [0001] The invention relates to an antibacterial drug based on the C-terminal connection of an antimicrobial peptide, belonging to the technical field of biomedicine. Background technique [0002] 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 a class of 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 contents, which is difficult for bacteria to overcome. Therefore, antimicrobial peptides are considered to be a class of antibacterial drugs with great potential. At present, natural antimicrobial peptides have not been used clinically, mainly becau...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K47/58A61K47/59A61K38/17A61P31/04A61P35/00
CPCA61K47/60A61K47/58A61K47/59A61K38/1767A61K38/1729A61K38/1703A61P31/04A61P35/00
Inventor 元冰杨恺邓智雄
Owner SUZHOU UNIV
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