Cyclization-Based Optimization of the Antimicrobial Peptide YD Yields a Nanomolar Inhibitor of Pulmonary Fibrosis

Pulmonary fibrosis is a common pathological outcome of various lung diseases, and therapeutic options limited. In view of the anti-inflammatory activity of antimicrobial peptides and the role of inflammation in pulmonary fibrosis, herein, we investigated the therapeutic potential of the antimicrobial peptide YD against pulmonary fibrosis for the first time. To improve its druggability, the structure of YD was optimized. Based on alanine scanning and cleavage site mapping, YD was truncated and modified with unnatural amino acids, thereby significantly enhancing its stability. Cyclization further improved its pharmacokinetic profile and in vivo efficacy. The optimized cyclic peptide CYP9 potently inhibited myofibroblast activation, epithelial–mesenchymal transition, and extracellular matrix synthesis at nanomolar concentrations. It exhibited an extended half-life and the ultralow effective dose of 0.02 mg/kg. Mechanistic studies revealed CYP9 effectively inhibits the TGF-β/Smad and MAPK signaling pathway. This study identifies the peptide CYP9 as a promising candidate for treating pulmonary fibrosis.