Therapeutic potential of a phospholipase D1 inhibitory peptide fused with a cell-penetrating peptide as a novel anti-asthmatic drug in a Der f 2-induced airway inflammation model

Asthma is a chronic lung disease that causes airflow obstruction due to airway inflammation. However, its therapeutics remain inadequate. We previously reported that phospholipase D1 (PLD1) is a key enzyme involved in the production of pro-inflammatory cytokines in airway inflammation induced by the house dust mite allergen Dermatophagoides farinae 2 ( Der f 2). We also revealed that PLD1 is specifically inactivated by AP180 (assembly protein, 180 kDa) and identified the PLD1-specific binding motif (TVTSP) of AP180. Therefore, the aims of this study were to develop a novel anti-asthmatic agent that could suppress airway inflammation by inhibiting PLD1 and examine its acute and chronic toxicity. We designed TAT-TVTSP, a PLD1-inhibitory peptide fused with a cell-penetrating peptide (CPP) delivery system. TAT-TVTSP was efficiently delivered to bronchial epithelial cells and significantly reduced Der f 2-induced PLD activation and Interleukin 13 (IL-13) production. Intranasally administered TAT-TVTSP was also efficiently transferred to airway tissues and ameliorated airway inflammation in a Der f 2-induced allergic asthma mouse model. Moreover, we investigated the safety of TAT-TVTSP as a therapeutic agent through single- and repeated-dose toxicity studies in a mouse model. Taken together, these results indicated that a PLD1-inhibitory peptide fused with a cell-penetrating peptide may be useful for treating allergic inflammatory asthma induced by house dust mites (HDMs). Allergic asthma: Drug to tackle allergy-triggered inflammation A drug that targets a key enzyme involved in airway tissue inflammation shows promise in the treatment of allergic asthma. The enzyme phospholipase D1 (PLD1) triggers airway inflammation in allergic asthma brought on by house dust mites. Joong-Soo Han at Hanyang University in Seoul, Eung-Gook Kim at Chungbuk National University, Cheongju, South Korea, and co-workers have developed a treatment aimed at suppressing PLD1 and trialed the drug on mouse models of dust-mite allergy. The team designed a carrier system capable of accurately delivering a PLD1-inhibitory peptide to airway tissues and cells. They found that airway inflammation was significantly reduced in the treated mice. The drug appeared to be relatively safe when used in repeated doses, although further investigations are needed to verify this. The team hope their treatment will improve therapies for allergic asthma.