Myristoylated Cathelicidin-DM Fused With ANG1-7: A Novel Self-Assembling Antimicrobial Peptide for the Treatment and Mechanism of Diabetic Infected Wounds.

Abstract

Diabetic wounds, due to severe vascular dysfunction, persistent inflammatory responses, and susceptibility to microbial infections, exhibit delayed healing and pose a significant challenge to human health. Diabetic wounds face delayed healing and significant health challenges due to vascular dysfunction, persistent inflammation, and infection susceptibility. Therefore, the development of drugs with antibacterial capabilities, as well as the ability to effectively regulate inflammation and promote angiogenesis, is of great importance. In this study, a novel antibacterial peptide (named MYR-DM-ANG1-7) was designed. It is composed of the coassembly of myristoylated antibacterial peptide cathelicidin-DM and angiotensin 1-7 (ANG 1-7). This novel antibacterial peptide demonstrates antibacterial activity against both Escherichia coli and Staphylococcus aureus bacteria and can even effectively inhibit the formation of biofilms. In vitro experiments confirmed that MYR-DM-ANG1-7 can promote the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), reduce the level of oxidative stress, alleviate the increase in mitochondrial membrane potential caused by high glucose (HG) and lipopolysaccharide (LPS), and decrease the expression of proinflammatory cytokines IL-6 and TNF-α. Western blot experiments confirmed that MYR-DM-ANG1-7 activates PI3K by targeting the membrane receptor Mas, thereby activating AKT, which ultimately promotes the activation of eNOS to produce nitric oxide (NO), thereby enhancing the angiogenic capacity of HUVECs. In vivo experiments showed that the local application of MYR-DM-ANG1-7 significantly improved the healing of infected diabetic wounds in mice, including increased wound healing rate, reduced inflammatory cell infiltration, and promoted collagen fiber and blood vessel formation. In summary, this study successfully constructed a multifunctional novel self-assembling antibacterial peptide that can effectively regulate oxidative stress, inflammation, and angiogenesis to promote the repair of diabetic infected wounds. This research provides a brand new self-assembling lipopeptide therapeutic strategy for the treatment of diabetic infected wounds.