This study investigates the impact of tryptophan substitution on the properties of the Medisin family peptide MS-PT. By substituting hydrophobic amino acids in MS-PT1 with tryptophan, a series of derivative peptides were synthesized. Among them, the 7W peptide stood out with its unique N-terminal random curl and α-helix structure. In vitro, 7W effectively inhibited the secretion of pro-inflammatory cytokines like IL-6 and TNF-α in LPS-induced Membrane-Proximal Macrophages (MPMs) by blocking the MAPK/NF-κB signaling pathway. It also exhibited stronger antimicrobial activity against Gram-positive bacteria compared to the parent peptide MS-PT1, with good safety as indicated by a low hemolysis rate. In vivo, in ... More
This study investigates the impact of tryptophan substitution on the properties of the Medisin family peptide MS-PT. By substituting hydrophobic amino acids in MS-PT1 with tryptophan, a series of derivative peptides were synthesized. Among them, the 7W peptide stood out with its unique N-terminal random curl and α-helix structure. In vitro, 7W effectively inhibited the secretion of pro-inflammatory cytokines like IL-6 and TNF-α in LPS-induced Membrane-Proximal Macrophages (MPMs) by blocking the MAPK/NF-κB signaling pathway. It also exhibited stronger antimicrobial activity against Gram-positive bacteria compared to the parent peptide MS-PT1, with good safety as indicated by a low hemolysis rate. In vivo, in the CLP-induced sepsis mouse model, 7W alleviated lung and liver injury, suppressed the expression of inflammatory factors in serum and tissues, and had a relatively long plasma half-life of 46.8 h. Mechanistically, 7W interacted preferentially with bacterial mimic membranes and LPS, and its anti-inflammatory effect might be mediated by binding to TLR4. These findings not only clarify the role of tryptophan substitution in modulating peptide properties but also offer a new strategy for the development of multifunctional antimicrobial peptides, suggesting that 7W has great potential as a therapeutic agent for sepsis and other inflammatory diseases.
