天然产物asperphenamate衍生物抗肺纤维化作用的评价  

Evaluation of anti-pulmonary fibrotic effect of a natural product asperphenamate derivative

作　　者：邹春阳 王垚 门金玉[3] 陈晨 阮馨慧 袁雷[3] ZOU Chunyang;WANG Yao;MEN Jinyu;CHEN Chen;RUAN Xinhui;YUAN Lei(Department of Pharmacy,Liaoning Vocational College of Medicine,Shenyang 110101,China;Liaoning Institute of Basic Medicine,Shenyang 110101,China;Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]辽宁医药职业学院药学系,辽宁沈阳110101 [2]辽宁省基础医学研究所,辽宁沈阳110101 [3]沈阳药科大学,辽宁沈阳110016

出　　处：《沈阳药科大学学报》2022年第9期1053-1058,共6页Journal of Shenyang Pharmaceutical University

基　　金：辽宁省教育厅研究项目(LJKZ1316)。

摘　　要：目的为了发现具有新颖作用机制的抗肺纤维化活性分子,基于前期建立的asperphenamate化合物库,选取具有成药性的衍生物研究其对于组织蛋白酶(cathepsins)的抑制作用,进一步评价其体内抗肺纤维化能力。方法利用荧光底物方法,以asperphenamate为对照药,筛选衍生物对于组织蛋白酶的抑制能力。进而利用H&E、Masson染色及免疫组化染色方法评价体内抗肺纤维化作用。结果组织蛋白酶活性测试结果表明,A-环邻羟基取代衍生物3a活性最优,其对cathepsin L的作用是对照药的8.5倍。进一步通过H&E、Masson染色及免疫组化染色方法揭示了3a具有明显的体内抗肺纤维化作用。结论化合物3a的发现为开发抗肺纤维化药物提供了新的思路。Objective To discovery anti-fibrotic agent with novel mechanism of action,the derivatives with better druggability were chosen to screen their inhibitory effects on cathepsins and further evaluate the antifibrotic ability in vivo based on the asperphenamate-type compound library.Methods Asperphenamate was selected as positive control.The cathepsin inhibitory ability of all derivatives were screened utilized by fluorescent substrate method.Further,H&E,Masson staining assay and immunohistochemical staining were applied to investigate in vivo antifibrotic effect.Results The cathepsin inhibitory activity assay results showed that o-hydroxyl substituted derivative in A-ring of asperphenamate 3 a displayed the most potent inhibitory potency against cathepsin L among all tested derivatives,which was 8.5-fold more potent than control group.The in vivo antifibrotic ability of 3 a was further confirmed by H&E,Masson staining assay and immunohistochemical staining.Conclusion The discovery of compound 3 a provides a novel idea for the development of anti-fibrotic drugs for the treatment of idiopathic pulmonary fibrosis.

关 键 词：特发性肺纤维化 组织蛋白酶抑制剂 asperphenamate 分子对接 体内抗纤维化作用 

分 类 号：R914[医药卫生—药物化学]