Studies On Wound Healing-promoting Properties Of Antimicrobial Peptides Derived From Tachykinin

Chronic wounds treatment bring great pressure to the patients and society.And Bacterial infections will further delay cutaneous wound healing.Due to the emergence of resistant bacteria,the treatment effect of the traditional antibiotics for wound infection is always unsatisfactory.Therefore,developing novel anti-infection drugs is extremely urgent.Because of the advantages of unique mechanism,not easy to produce resistance,antimicrobial peptides will become one of the promising agents for infected wound treatment.Tachykinins belong to neuropeptides involved in a variety of physiological processes.They are widely distributed in the human body,which play an important role in injury repair.And the antimicrobial activity of tachykinins is weak,limiting its use for the treatment of wound infection.They have structural characteristics similar to antimicrobial peptides(positively charged,amphiphilic).Thus,tachykinins have transformation potential in the antimicrobial activity,and are expected to develop lead compounds with antimicrobial and wound-healing properties.In this study,we take human Hemokinin-1 and substance P as the research objects to design antimicrobial peptides with anti-infection and healing activities,which provides a thought for the development of drugs for treating chronic wound infections.The early work of the research group was to introduce LKKW sequence(leucine-lysine-lysine-tryptophan)at the N-terminus of hHK-1 to increase the number of positive charges and hydrophobicity,designed and synthesized a series of analogues.And the antibacterial activity and mechanism of the analogues were studied.The results showed that the modified hHK-1 analogs had an enhanced antibacterial activity.The hHK-1 series retains the C-terminal sequence and may have the activity of promoting wound healing.Therefore,we studies the wound healing,anti-infection,cell proliferation and migration activities of the hHK-1 series,and finally screened out the analogs HK-3 and HK-5 with anti-wound infection and wound healing properties.Previous studies have shown that although substance P(SP)can significantly promote wound healing,its antimicrobial activity is weak.However,pexiganan(MSI-78)with a strong antibacterial activity can treat diabetic foot ulcer infection.Hence,we introduced the active fragments of MSI-78 at the N-terminus of SP and designed a series of analogues.We tested antimicrobial activity and cytotoxicity of MSI-78 and its analogues in vitro.And we found that MSI-78 series have high antimicrobial activity and low cytotoxicity.MSI-78 and its analogues can inhibit the biofilm formation of Staphylococcus aureus.In the mouse experiments,BM-5 not only promoted wound healing but also cared infected wound healing.Analogues HK-3,HK-5 and BM-5 can be used as a leading compound of antimicrobial peptides with anti-infection and wound healing properties,which provides a new method for the development of chronic wound drugs.