Innovative peptide therapeutics targeting IL17RA to regulate inflammatory responses.

Interleukin-17 receptor A (IL17RA) is a critical mediator of pro-inflammatory cytokine signaling and a key immune checkpoint in autoimmune diseases. While monoclonal antibodies targeting IL17RA have demonstrated clinical efficacy, their high costs, complexity in production, and lack of oral bioavailability present significant limitations. In response to these challenges, we developed AL-8(0), a novel peptide specifically designed to inhibit the IL17A-IL17RA signaling pathway. AL-8(0) was synthesized with high purity and systematically evaluated for its binding affinity and anti-inflammatory activity. Biophysical and cellular assays confirmed the peptide's strong affinity for IL17RA and its ability to inhibit inflammatory cytokine production in IL17RA-expressing monocyte-macrophages and keratinocytes. Moreover, its anti-inflammatory effects were com-parable to IL17RA-targeting monoclonal antibodies and were dependent on IL17RA expression, as demonstrated by experiments using IL17RA-deficient cells. These results underscore AL-8(0)'s potential as a targeted therapeutic for autoimmune diseases, offering a peptide-based alternative with lower antigenicity, improved scalability, and potential for oral administration. This study lays the groundwork for further development of AL-8(0) and similar peptides as innovative treatments for inflammatory disorders driven by the IL17A-IL17RA pathway.