超短环肽Cy<sub>RL-QN15</sub>作为TLR4拮抗剂加速口腔溃疡愈合
Zeqiong Ru, Yutong Wu, Wu Yu-Tong, Yang Chong-Yu, Yang Ya-Ting, Li Ya-Jie, Liu Min, Peng Ying, Yang Yu-Liu, Wang Jun-Yuan, Jia Qiu-Ye, Li Yuan-Sheng, Fu Zhe, Yang Mei-Feng, Tang Jing, Fan Yan, Liu Cheng-Xing, Su Wen-Rou, He Li, Ying Wang, Wang Ying, Yang Xin-Wang, 昆明医科大学基础医学院医学生物化学与分子生物学系, 云南 昆明650500, 中国, 云南民族大学民族医学院民族药用资源化学重点实验室, 民族药用内生植物天然产物合成生物学重点实验室, 云南 昆明650504, 中国, 云南云科特色植物提取实验室有限公司, 云南 昆明 650106, 中国, 昆明医科大学第一附属医院皮肤科, 云南 昆明 650032, 中国
Abstract
Oral ulcers (OUs) are prevalent oral mucosal lesions characterized by pain and burning sensations, and remain clinically challenging due to limited therapies, necessitating innovative treatment approaches. CyRL-QN15, a novel ultra-short cyclic heptapeptide, has recently shown efficacy in skin repair, diabetic foot ulcer healing, and hair regeneration. This study evaluated the mucosal regenerative efficacy of CyRL-QN15 using a rat OU model and a primary oral epithelial cell inflammation model. Results revealed that CyRL-QN15 accelerated OU healing by orchestrating immune-epithelial crosstalk mechanisms, including suppression of inflammatory cytokine release from macrophages and neutrophils, reduction of pro-inflammatory factor secretion by oral epithelial cells, and enhancement of their proliferative and migratory capacities. Mechanistically, through alanine scanning mutagenesis and microscale thermophoresis validation, CyRL-QN15 directly bound to Toll-like receptor 4 (TLR4) via a methionine residue (Kd = 2.64 µM), inhibiting the MyD88/NF-κB pathway. As the first reported ultra-short cyclic heptapeptide TLR4 antagonist, CyRL-QN15 uniquely modulates the inflammation-repair balance, offering both a novel therapeutic candidate and mechanistic insights for TLR4-based OU intervention.