PEGylated Peptide for Targeted Inhibition of Human Antigen R as a Novel Therapeutic Strategy for Psoriasis: A Proof-of-Concept Study.

Abstract

Introduction: Psoriasis, characterized by dermatological manifestations, exhibits a systemic impact through its association with serious comorbidities, including inflammatory arthritis, cardiovascular and metabolic diseases, and psychiatric disorders. Current high-cost traditional therapies primarily involve antibodies against psoriasis-associated cytokines. Human antigen R (HuR), an RNA-binding protein that regulates the expression of upstream inflammatory cytokines, is overexpressed in immune disorders. Oligopeptide-based drugs that specifically interact with proteins to block downstream gene expression via structural interactions have garnered significant attention. In this study, we report a peptide-based polymer to target HuR and evaluated their efficacy in treating imiquimod (IMQ)-induced psoriasis-like dermatitis in mice ears.

Methods: Specifically, the HuR-inhibiting peptide (HIP) is PEGlated to obtain methoxypolyethylene glycol-block-poly(γ-benzyl glutamate) (mPEG-b-PBLG) amphiphilic block copolymer. The self-assembly of the mPEG-b-PBLG block copolymer facilitates the formation of polymeric nanoparticles (NPs) in aqueous solutions, resulting in the improvement of the stability and bioactivity of the oligopeptide.

Results: Macroscopic and histological analyses demonstrated that the oligopeptide significantly alleviates the symptoms in psoriasis model mice. Furthermore, the levels of the key cytokine IL-23 and the growth factor VEGF are downregulated. Notably, the HIP effectively targeted the ear skin and did not induce apparent organotoxicity.

Discussion: The promising results demonstrated in this proof-of-concept study provide strong evidence supporting the targeted inhibition of HuR via PEGylated peptide. The observed efficacy in mitigating key inflammatory markers (VEGF and IL-23) highlights the potential of this approach to offer superior specificity and reduced systemic side effects compared to current broad-spectrum immunosuppressants. This HuR-targeting strategy offers a potentially low-cost and effective therapeutic approach for psoriasis patients.