Design and discovery of a novel interleukin-11 derived peptide with antagonistic activity for the treatment of renal fibrosis.

Interleukin-11 (IL-11) has emerged as a novel therapeutic target for renal fibrosis, a devastating condition with a significant unmet clinical need. In this study, we presented the first exploration of peptide antagonists derived from the C-terminal region of IL-11, which is highly conserved across species and is functionally implicated in receptor engagement. Through the formation of a key lactam linkage, P19 was generated. P19 displayed an antagonistic activity with an IC50 value of 6.3 ± 0.82 μM and a binding affinity with a KD value of 9.4 μM for hIL-11Rα. Further, we elucidated the importance of the lactam ring through molecular dynamics (MD) simulations. Additionally, P19 exhibited significant anti-renal fibrosis in in vivo models by reducing the phosphorylation of ERK1/2. Finally, P19 exhibited favorable safety profiles, with no obvious tissue toxicity in mice. This study offers a new strategy for IL-11 antagonists design and provides a promising lead for developing anti-renal fibrosis agents.