Chemical Design Of Multivalent Antimicrobial Peptides And Their Biomedical Applications

At present,bacterial resistance caused by the abuse of antibiotics has become a worldwide problem in the treatment of clinical bacterial infections.In response to this problem,antimicrobial peptides（AMP）with broad-spectrum antimicrobial activity and resistance to resistance have developed into one of the most promising alternatives to antibiotics.The main antibacterial mechanism of antimicrobial peptides is the electrostatic interaction between polypeptide molecules and bacterial membranes,which induces bacterial membrane damage and leakage of cell contents,thereby killing bacteria.However,its antibacterial efficiency is concentration-dependent,easy to be hydrolyzed and inactivated,and high production costs restrict its practical application.Therefore,how to improve the current shortcomings of antimicrobial peptides and design antimicrobial peptide molecules with high efficiency,low toxicity and not easy to inactivate has extremely important research value and clinical significance.The"multivalent effect"is to significantly enhance the selectivity and binding force between ligand molecules and cells through the interaction of multiple ligands and receptors,thereby improving the biological effects of ligand molecules.For example,by modifying multiple antimicrobial peptides on long-chain macromolecules,with the help of the"multivalent effect"of multiple antimicrobial peptides and bacterial membranes,it is expected to significantly improve the interaction of antimicrobial peptides with bacteria and membranes and enhance the antibacterial efficiency of antimicrobial peptides.In addition,the multivalent electrostatic effect of long-chain multiple antibacterial molecules is conducive to the functionalization of antibacterial molecules and the design of antibacterial materials.This undoubtedly provides new strategies and ideas for the development of antibacterial drugs and the construction of biomaterials.In this paper,based on the antibacterial mechanism of antimicrobial peptides and the biological"multivalent effect",polymer molecules with multivalent antimicrobial peptide units are controllably designed.And based on the electrostatic effect of the multivalent antimicrobial peptide polymer,an antimicrobial hydrogel with a dynamic crosslinking network is further prepared.In this paper,the antibacterial enhancement effect of multivalent antibacterial peptide polymers and the medical application potential of dynamic antibacterial hydrogels are explored in detail.The specific research content is as follows:1.Design and Performance study of（RW）₃Linear Multivalent Antimicrobial Peptide PolymerUsing propargyl acrylamide（PRMA）as the monomer,a clickable linear polymer was controllably synthesized by RAFT polymerization.Then a multivalent antimicrobial peptide polymer（PAMP）was prepared by click modifying the polymer with the free（RW）₃-N₃.The antibacterial properties and cytotoxicity of PAMP have been studied.The results show that PAMP can greatly enhance the antibacterial activity compared to the ordinary AMP.The minimum inhibitory concentration（MIC）of PAMP against Escherichia coli is reduced to2.5-5?M,which is 8-16 times higher than that of free AMP.The MIC of PAMP against Staphylococcus aureus is reduced to 2.5?M,which is 8 times higher than that of free AMP.The antimicrobial efficiency increases more obviously with the increase of the valence of the antimicrobial peptide on the PAMP molecule.At the minimum inhibitory concentration,PAMP shows less cytotoxicity to L929 cells,and only a few cells were damaged in the live and dead stained image of cells.At the same time,L929 cells still have good proliferation activity after 5days of continuous culture.2.Preparation and performance study of dynamic hydrogel based on（RW）₃linear multivalent antimicrobial peptide polymerThe Polyethylene glycol（PEG）chain was modified with AMP by Michael addition reaction.An antibacterial hydrogel（PAMP-Gel）with self-healing,injectable and antibacterial properties were prepared successfully by the cross-link of the inorganic nanosheets and the PEG-based PAMP through electrostatic interaction.The antibacterial properties,cytotoxicity and mechanical properties of PAMP-Gel were studied.The results show that PAMP-Gel can release antibacterial peptides to kill bacteria,and can also show good antibacterial properties in animals and promote wound healing.Compared with PAMP molecules,the cell survival rate after PAMP-Gel culture is as high as 95%,and the cell can proliferate normally.The PAMP-Gel has more excellent biocompatibility.At the same time,PAMP-Gel whose storage modulus can reach 501.5Pa,has excellent mechanical properties and has self-healing and injectable properties,and can complete self-healing within 1h.