De novo discovery of cyclic peptide inhibitors of IL-11 signaling

Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has potential pro-inflammatory and pro-fibrotic roles in pulmonary, hepatic, cardiovascular, renal and intestinal disease pathogenesis, including oncogenesis. The potential for therapeutic intervention in these disease spaces has therefore made the IL-11 signaling axis an attractive target in drug discovery, and antibody inhibitors of IL-11 signaling are currently under evaluation in Phase I/II clinical trials. While lower molecular weight small molecule and peptide inhibitors may offer the potential for improved tissue penetration, developability and manufacturing cost compared with a protein therapeutic, reports of such chemical matter in the literature are limited. In this work, a series of cyclic peptides derived from phage display biopanning campaigns against both IL-11 and its cognate receptor IL-11Rα are presented. The most active IL-11 binder (peptide 4, K_D 140 nM) exhibited inhibition of IL-11/IL-11Rα dimerization in a biochemical AlphaLISA assay (K_i 300 nM), and alanine scanning was carried out on this sequence to identify residues important for target binding and inhibitory activity. Further structural optimization yielded lead peptide 15 (K_i 180 nM), which exhibited at least 70-fold greater activity than IL-11 inhibitors previously reported in the literature. The de novo peptide macrocycles presented serve as a robust starting point for development of therapeutic inhibitors of the IL-11/IL-11Rα interaction.