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

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.