Rational design and therapeutic potential of MyD88 inhibitory peptide in psoriasis

Myeloid differentiation primary-response 88 (MyD88) is a crucial adaptor protein for initiating immune responses via Toll-like receptors (TLRs). This study employed a rational peptide design approach to develop MyD88 inhibitory peptides targeting the MyD88 interaction interface. The designed peptide, MyDIP2–4, was evaluated for its efficacy in inhibiting MyD88-dependent signaling in human and mouse cell lines. In vitro analyses demonstrated that MyDIP2–4 effectively inhibited MyD88-mediated signaling in both the TLR- and IL-1R-mediated pathways. Surface plasmon resonance experiments confirmed that MyDIP2–4 specifically interacted with MyD88 in a concentration-dependent manner. In an imiquimod-induced psoriasis model, MyDIP2–4 significantly inhibited disease progression, as evidenced by a reduction in psoriasis area and severity index scores. Histological staining revealed decreased epidermal thickness, while immunohistochemical analysis showed downregulation of IL-17 levels following treatment. These findings suggest that MyDIP2–4 is a promising candidate for the treatment of psoriasis. Targeting the Toll/interleukin-1 receptor domain of MyD88 through rational peptide design offers a novel strategy for developing therapeutics for autoimmune diseases.