Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses.
Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses.
复制标题
罂粟碱被鉴定为高迁移率族盒 1/受体晚期糖基化终产物相互作用的抑制剂，可抑制高迁移率族盒 1 介导的炎症反应。
DOI：
10.1016/j.bbrc.2019.01.136
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Tanuma S.
中科院分区：
文献类型：
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作者：
Tamada K;Nakajima S;Ogawa N;Inada M;Shibasaki H;Sato A;Takasawa R;Yoshimori A;Suzuki Y;Watanabe N;Oyama T;Abe H;Inoue S;Abe T;Yokomizo T;Tanuma S.
高迁移率族蛋白1（HMGB 1）在细胞感染和损伤期间从免疫细胞和垂死细胞分泌，与晚期糖基化终产物（AGEs）受体的相互作用似乎对急性和慢性炎症性疾病至关重要。在这里，我们设计了一个独特的环状β-发夹肽（Pepb 2），它模拟了预测的HMGB 1的RAGE结合结构域。Pepb 2竞争性抑制HMGB 1/HMGB 2相互作用。然后，我们确定罂粟碱作为Pepb 2模拟物通过在硅三维结构相似性筛选从DrugBank库。发现罂粟碱直接抑制HMGB 1/HMGB 2相互作用。在小鼠巨噬细胞样RAW264.7细胞和骨髓源性巨噬细胞中，它还抑制HMGB 1介导的促炎细胞因子IL-6和TNF-α的产生。此外，罂粟碱降低盲肠结扎穿孔诱导的脓毒症模型小鼠的死亡率。总之，这些发现表明罂粟碱可能成为一种有用的治疗HMGB 1/RAGE介导的脓毒症和其他炎症性疾病的药物。
The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic β-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic byin silico3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.