Novel Peptide Therapy for Psoriasis Addresses Systemic Inflammation Beyond Symptom Relief

Despite ongoing efforts to develop biologic treatments targeting the underlying immune mechanisms of moderate to severe plaque psoriasis, current therapies remain focused primarily on symptom relief. Common options include phototherapy, corticosteroids (both topical and systemic), vitamin D analogues, retinoids, and dithranol—each with notable limitations. This underscores the need for new, more effective therapies.

Researchers have identified two pharmacophores (sequences of three amino acids) within peptide inhibitor of transendothelial migration (PEPITEM), a 14–animo acid peptide that is released by B lymphocytes during an inflammatory response, such as with psoriasis. These pharmacophores could represent a novel treatment option focused on systemic relief instead of symptom relief.

“PEPITEM has powerful regulatory functions in the inflammatory response, where it operates to limit the number of pro-inflammatory effector T-cells and macrophages that traffic to tissues under inflammatory conditions,” the researchers noted. The topical application of PEPITEM tripeptide sequence derivatives provide “powerful disease-modifying actions in psoriatic disease.”

The results were published in Pharmacological Research.

According to the researchers, topical administration of PEPITEM derivatives was not previously tested. They applied PEPITEM and one of the derivatives, SVT[NH-ethyl], topically in a mouse model of psoriasis. PEPITEM and SVT[NH-ethyl] showed ability to penetrate the skin and efficacy in epidermal stroma and resulted in an approximately 50% reduction in disease according to the Psoriasis Area and Severity Index-50 tool.

Topical application of PEPITEM not only reduced local inflammation but also had systemic effects, such as reducing disease-related splenomegaly and limiting the expansion of CD4+, CD8+, Th1, and Th17 T-cell populations in the spleen. In addition, it altered T-cell function in skin-draining lymph nodes by reducing the production of effector cytokines in response to stimulation.

Because these systemic immune responses are hallmarks of chronic inflammation in immune-mediated inflammatory diseases, these findings suggest therapeutic benefits beyond the skin. They also raise the possibility that other immune-related disease states, such as arthritis, could potentially be treated by means of topical delivery.

In this context, PEPITEM and its derivatives show steroid-like activity, including suppression of leukocyte trafficking and inflammatory cytokines, supporting its use alongside existing therapies.

“Taken together with other reports on the efficacy of PEPITEM, this study paves the way for the development and translation of a novel class of anti-inflammatory agents which may have utility in a broad range of autoimmune and chronic inflammatory diseases,” the researchers concluded.

Reference

Saviano A, et al. Pharmacol Res. 2025;213:107624. doi:10.1016/j.phrs.2025.107624