Synthesis and Activity Evaluation of All-Hydrocarbon Stapled Peptides with Improved Anti-Inflammatory Efficacy via the NF-κB Signaling Pathway and Attenuated Cytotoxicity

Discovering effective anti-inflammatory peptides targeting the NF-κB pathway is a critical research priority. Herein, a docking study was carried out to screen 25 original linear peptides. Next, 44 novel stapled peptides via the all-hydrocarbon cross-linking strategy were designed and synthesized. 75%-80% stapled peptides displayed reduced cytotoxicity and improved anti-inflammatory activity over the original peptides <i>in vitro</i>. Compared with Dex, <b>s-12s</b> significantly inhibited the expression of proinflammatory mediators <i>in vitro</i> and <i>in vivo</i>. Notably, <b>s-12s</b> also protected mice from LPS-induced mortality and acute organ injury. Mechanistically, <b>s-12s</b> reduced LPS-induced activation of the NF-κB pathway. Moreover, surface plasmon resonance and MD simulations have determined the possibility of NF-κB as a target for <b>s-12s</b>. Therefore, <b>s-12s</b> could be used as a promising therapeutic candidate for inflammatory disorders. Meanwhile, these results have proven that the all-hydrocarbon stapling of anti-inflammatory peptides was a feasible approach for the future development of anti-inflammatory therapeutics.