Novel IL-11-derived peptide P19 antagonizes IL-11Rα and reduces renal fibrosis in vivo

Chronic kidney disease (CKD) affects 9-13% of the global population, with renal fibrosis being a devastating, progressive component driven by inflammation and oxidative stress. Current therapeutic strategies often fall short, highlighting a significant unmet clinical need for effective anti-fibrotic agents. Interleukin-11 (IL-11) has recently emerged as a novel and promising therapeutic target due to its critical role in promoting fibrosis across various organs, including the kidney. This study addresses the gap in specific peptide-based antagonists targeting the IL-11 pathway for renal fibrosis treatment.

Researchers designed and synthesized P19, a novel peptide antagonist derived from the C-terminal region of IL-11, incorporating a key lactam linkage for stability and activity. They evaluated P19's antagonistic activity against hIL-11Rα using in vitro assays, determining its IC50 and KD values. Molecular dynamics (MD) simulations were employed to elucidate the importance of the lactam ring in its mechanism. Furthermore, P19 was tested for anti-renal fibrosis effects in in vivo mouse models, with ERK1/2 phosphorylation measured as a key mechanistic readout. Safety profiles were also assessed in mice.

The novel IL-11-derived peptide P19 exhibited potent antagonistic activity against hIL-11Rα with an IC50 value of 6.3 ± 0.82 µM. Its binding affinity for hIL-11Rα was confirmed with a KD value of 9.4 µM. Molecular dynamics simulations underscored the critical role of the lactam ring in P19's function. In in vivo models, P19 demonstrated significant anti-renal fibrosis effects, specifically by reducing the phosphorylation of ERK1/2, a key signaling molecule implicated in fibrotic pathways. Importantly, P19 exhibited favorable safety profiles in mice, with no obvious tissue toxicity observed.

P19 significantly reduced renal fibrosis in in vivo models by inhibiting ERK1/2 phosphorylation, showing promise as an anti-fibrotic agent.