Moracin M derivative targeting PDE4 for the treatment of psoriasis

Phosphodiesterase-4 (PDE4), a member of the phosphodiesterase superfamily, has highly important roles in cyclic nucleotide signaling pathways and a variety of skin disorders. Blocking PDE4 activity with PDE4 inhibitors increases intracellular cAMP levels and effectively relieves the skin inflammatory phenotype of psoriasis. However, traditional PDE4 inhibitors may cause adverse effects such as gastrointestinal reactions. Natural products typically exhibit safety profiles and structural novelty, which are particularly advantageous for drug discovery. LW, a derivative of the natural product Moracin M, was found to have favorable PDE4 inhibitory activity (PDE4 IC 50 = 54 nM). Examination of LW in psoriasis treatment demonstrated good anti-inflammatory effects in cellular models. In an imiquimod-induced mouse model, LW treatment markedly improved psoriatic symptoms, as evidenced by increased PASI scores and ameliorated skin pathology. Moreover, LW significantly downregulated Inflammatory factors in the serum and alleviated spleen damage. Therefore, LW has substantial therapeutic potential, through effectively decreasing inflammatory factor levels and ameliorating psoriatic skin phenotypes. Our findings support LW as a potential candidate compound for developing new psoriasis treatments.