A novel peptide-compound conjugate alleviates endotoxin-induced inflammation via NF-κB/MAPK modulation

The anti-inflammatory ability of a novel peptide-compound conjugate, 2IP5MP-CW, synthesized by fusing 2-isopropyl-5-methylphenoxy acetic acid with cysteine and tryptophan, was investigated in this study. 2IP5MP-CW markedly inhibited the growth of Escherichia coli and Staphylococcus aureus and exhibited potent antioxidative activity by suppressing reactive oxygen species production and mitigating oxidative DNA damage induced by lipopolysaccharide (LPS). In RAW 264.7 macrophages, 2IP5MP-CW significantly reduced LPS-induced TNF-α production and suppressed nitric oxide (NO) generation as well as the expression of inflammation-related proteins iNOS and COX-2. The compound also attenuated the phosphorylation of ERK, JNK, NF-κB p65, IKKβ, and IκBα, thereby blocking the nuclear translocation of phosphorylated NF-κB p65. In an LPS-induced mouse model of pulmonary inflammation, 2IP5MP-CW treatment reduced the phosphorylation of ERK, JNK, NF-κB p65, IKKβ, and IκBα in LPS-challenged lung tissue. Furthermore, it markedly attenuated TNF-α production and downregulated iNOS and COX-2 expression. Histological examination further confirmed that 2IP5MP-CW alleviated inflammatory cell infiltration and tissue injury. Collectively, these findings demonstrate that 2IP5MP-CW exerts potent anti-bacterial, anti-oxidative, and anti-inflammatory effects by suppressing LPS-induced TNF-α and NF-κB/MAPK signaling, highlighting its therapeutic potential against LPS-mediated inflammatory lung injury. KEY MESSAGES: A novel peptide-compound conjugate, 2IP5MP-CW, was designed and synthesized. 2IP5MP-CW exhibited in vitro and in vivo anti-bacterial activity against E. coli and S. aureus. 2IP5MP-CW showed anti-oxidative activity by suppressing ROS production. 2IP5MP-CW demonstrated anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. 2IP5MP-CW exhibited anti-inflammatory efficacy in a pulmonary inflammation mouse model.