Anti-inflammatory effect of novel polypeptide WMX-8 through specific blockade of the IL17RA signaling pathway

Abstract

Interleukin-17 receptor A (IL17RA) acts as a core mediator of pro-inflammatory signaling and contributes crucially to the pathogenesis of autoimmune disorders including psoriasis and rheumatoid arthritis. Monoclonal antibodies against IL17RA have achieved clinical application, yet their clinical utility is restricted by multiple drawbacks: high production cost, complicated manufacturing procedures, mandatory injection delivery, and absent oral bioavailability. To overcome these bottlenecks, this study develops a novel inhibitory peptide WMX-8 intended to specifically disrupt the binding between IL17A and IL17RA. The polypeptide WMX-8 was rationally designed and chemically synthesized, followed by purification to obtain high-purity samples. A series of systematic in vitro biological assessments were conducted using IL17RA-expressing cell models (keratinocytes and monocyte-macrophages), alongside IL17RA-deficient cells as negative control groups. Biochemical and cellular assays verified that WMX-8 binds IL17RA with strong affinity and markedly suppresses the secretion of pro-inflammatory cytokines in IL17RA-positive keratinocytes and monocyte-macrophages. Its anti-inflammatory efficacy is equivalent to that of the reference anti-IL17RA monoclonal antibody. The inhibitory activity fully relies on IL17RA expression, since the anti-inflammatory effect disappears entirely in IL17RA-knockout cells. In addition, WMX-8 displays desirable pharmaceutical features, including low immunogenicity and convenient large-scale synthesis.This study validates the promising druggable properties of WMX-8 targeting the IL17A–IL17RA axis. Our findings lay a solid foundation for further preclinical investigation of peptide therapeutics against IL17A/IL17RA for the treatment of autoimmune diseases.