Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment

Abstract In recent years, the role of interleukin-11 (IL-11) in renal fibrosis has garnered considerable interest and is regarded as a promising therapeutic target for this condition. Herein, we explored the effects of replacing the oxidation-sensitive thioether moiety with a lactam bridge. By screening linker length and performing further optimization, we developed an analog, 4L6–16. This compound exhibited a high binding affinity for IL-11, with a KD value of 134 nM, along with enhanced antagonistic activity. Moreover, 4L6–16 demonstrated significant renoprotective effects in both in vitro and in vivo models of renal fibrosis, supporting its potential for further optimization to develop novel IL-11-targeted therapeutic agents.