CN112618531A - 炔丙基半胱氨酸在制备受体激动制剂中的用途 - Google Patents
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Abstract
本发明属生物医药技术领域，涉及炔丙基半胱氨酸新的药用用途，具体涉及炔丙基半胱氨酸在制备受体激动制剂中的用途，尤其涉及炔丙基半胱氨酸通过新的表面受体激动靶点及其通过该靶点发挥药效。本发明采用炔丙基半胱氨酸为药物活性成分，低浓度药物处理可在分子及细胞水平激动该表面受体，同时，所述受体产生优良的非酒精性脂肪肝炎保护的药效作用。本发明提供了炔丙基半胱氨酸（SPRC）发挥药效的新靶点，经药理活性测试表明其在体外具有良好的非酒精性脂肪肝及非酒精性脂肪肝炎的保护作用，可进一步制备防治肝病的药物。
Description
技术领域
本发明属生物医药技术领域，涉及炔丙基半胱氨酸新的药用用途，具体涉及炔丙基半胱氨酸在制备受体激动制剂中的用途。本发明提供了炔丙基半胱氨酸（SPRC）发挥药效的新靶点，经药理活性测试表明其在体外具有良好的非酒精性脂肪肝及非酒精性脂肪肝炎的保护作用，可进一步制备防治肝病的药物。
背景技术
现有技术公开了炔丙基半胱氨酸是大蒜中的主要成分烯丙基半胱氨酸的结构类似物。炔丙基半胱氨酸经初步药理学研究表明具有显著的心血管药理活性，具有潜在的药用价值。研究表明，炔丙基半胱氨酸可发挥多种药理药效作用，但有关药效作用靶点不甚明确，需进一步的研究证实。
研究表明，非酒精性脂肪肝炎是一种胰岛素拮抗和遗传易感密切相关的代谢应激性肝脏损伤，是无大量饮酒且损伤可弥散在整个肝脏的一组疾病，该疾患以肝细胞脂肪变性和脂质储积为主要特征，容易发展为肝硬化，与肝癌的发生有密切关系；研究还表明。日常过多的高糖高脂饮食会导致肝脏中脂肪的堆积并在非酒精性脂肪肝的发生过程中起到了重要的作用。
基于现有技术的现状，本申请的发明人拟提供新的防治肝病的药物，具体涉及炔丙基半胱氨酸新的药用用途，尤其涉及炔丙基半胱氨酸在制备受体激动制剂进一步用于防治肝病的药物中的用途。
发明内容
本发明的目的是基于现有技术的现状，提供新的防治肝病的药物，具体涉及炔丙基半胱氨酸新的药用用途，尤其涉及炔丙基半胱氨酸在制备受体激动制剂中的用途。
本发明采用炔丙基半胱氨酸为药物活性成分，低浓度药物处理可在分子及细胞水平激动该表面受体，实验证实所述的炔丙基半胱氨酸通过新的表面受体激动靶点及其通过该靶点发挥药效，经药理活性测试表明其在体外具有良好的非酒精性脂肪肝及非酒精性脂肪肝炎的保护作用，可用于制备受体激动制剂，进一步制备防治肝病的药物。
式（Ⅰ）
本发明中，确定一个炔丙基半胱氨酸（式（Ⅰ））的新靶点为表皮生长因子受体；该表皮生长因子受体是一个跨膜糖蛋白，具有配体诱导的酪氨酸蛋白激酶活性，它是ErbB这个保守党的受体受体家族的一个成员。
本发明以炔丙基半胱氨酸与表皮生长因子受体蛋白作分子相互作用测试（Biacore实验）确定两者可以直接相互作用，同时通过计算机分子模拟实验预测炔丙基半胱氨酸可以与表皮生长因子受体通过两个氢键相互作用；
本发明实验中，所述炔丙基半胱氨酸直接给药小鼠原代肝细胞可短时间内激活表皮生长因子受体，因此，炔丙基半胱氨酸原料药物可以直接结合表皮生长因子受体（EGFR）并短时间内激动该受体（磷酸化）从而发挥其药物机制；同时炔丙基半胱氨酸给药可以防止棕榈酸对肝细胞的损伤作用以及降低原代肝细胞对脂质的吸收，实验结果表明，炔丙基半胱氨酸可降低非酒精性脂肪肝的血脂以及非酒精性脂肪肝引起的肝脏损伤作用。
本发明提供了炔丙基半胱氨酸新的药用用途，经试验证明了炔丙基半胱氨酸通过激活表皮生长因子受体产生治疗非酒精性脂肪肝炎的作用，所述炔丙基半胱氨酸可制备受体激动制剂，进一步用于制备防治肝病的药物。
附图说明
图1：炔丙基半胱氨酸与表皮生长因子受体的直接相互作用（分子相互作用测试）。
图2：炔丙基半胱氨酸与表皮生长因子受体的计算机模拟相互作用方式。
图3：炔丙基半胱氨酸直接激活小鼠原代肝细胞中的表皮生长因子受体，同时防止肝细胞被棕榈酸损伤以及产生降脂作用，其中，* p < 0.05 炔丙基半胱氨酸与棕榈酸损伤组比较。
具体实施方式
实施例1
使用炔丙基半胱氨酸与表皮生长因子受体（EGFR）蛋白进行分子相互作用测试（Biacore实验），使用PBS溶解炔丙基半胱氨酸并制备浓度梯度溶液（78.125 μM - 625 μM），表皮生长因子受体（50 μg）蛋白使用PBS溶解后偶联至Biacore实验配对芯片（CM5芯片）上，炔丙基半胱氨酸浓度梯度（78.125 μM - 625 μM）经由Biacore程序设定进针，实验结果显示，炔丙基半胱氨酸可以浓度依赖性地发生直接相互作用。
实施例2
进一步评估炔丙基半胱氨酸与表皮生长因子受体之间的相互作用，使用计算机进行了分子对接研究，分子炔丙基半胱氨酸可以结合在野生型EGFR（PDB:2ITY）的活性位点中，如结合口袋表面图所示，SPRC（蓝色）与吉非替尼（易瑞沙，粉红色）具有相似的方向，SPRC的氮原子位于吉非替尼的吲哚氮原子的相同位置，其中预测NH和ASP 855之间的氢键具有相互作用，此外，SPRC的羰基与LYS 745可形成氢键，表明SPRC可以再两个氢键的帮助下直接靶向EGFR。
实施例3
使用胶原酶II配备肝脏消化液使用两步灌流消化法提取小鼠原代肝细胞并铺板于培养板中，次日炔丙基半胱氨酸（30 μM）直接处理小鼠原代肝细胞可短时间内（15 min）激活表皮生长因子受体，400 μM棕榈酸（10% BSA（W/L，无脂肪酸）溶解于0.1 M NaOH PBS配备棕榈酸母液，目测浓度为5 mM）处理小鼠原代肝细胞可产生明显脂质储积以及肝细胞损伤，而炔丙基半胱氨酸（10 ~ 30 μM）处理可以防止棕榈酸对肝细胞的损伤作用以及降低原代肝细胞对脂质的吸收。
Claims (6)
1.式（Ⅰ）的炔丙基半胱氨酸在制备受体激动制剂中的用途，
式（Ⅰ）。
2.根据权利要求1所述的用途，其特征在于，所述炔丙基半胱氨酸原料药物直接结合表皮生长因子受体EGFR并短时间内激动该受体即磷酸化。
3.根据权利要求1所述的用途，其特征在于，所述炔丙基半胱氨酸提高肝细胞活性，防止脂肪肝状态下的肝细胞损伤以及降低肝细胞对脂质的吸收。
4.根据权利要求1所述的用途，其特征在于，所述的受体激动制剂用于制备预防与治疗哺乳动物非酒精性脂肪肝及非酒精性脂肪肝炎的药物。
5.根据权利要求4所述的用途，其特征在于，所述哺乳动物为人。
6.根据权利要求4所述的用途，其特征在于，所述的非酒精性脂肪肝及非酒精性脂肪肝炎由高糖高脂饮食导致。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103284987A (zh) * | 2012-02-24 | 2013-09-11 | 复旦大学 | 炔丙基半胱氨酸及其类似物在制备防治心血管系统炎症相关疾病药物中的用途 |
| CN103284988A (zh) * | 2012-02-24 | 2013-09-11 | 复旦大学 | 炔丙基半胱氨酸及其类似物在制备治疗免疫相关炎症疾病药物中的用途 |
| CN111544426A (zh) * | 2019-02-12 | 2020-08-18 | 复旦大学 | 炔丙基半胱氨酸及其在制备新靶点药物中的用途 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103284987A (zh) * | 2012-02-24 | 2013-09-11 | 复旦大学 | 炔丙基半胱氨酸及其类似物在制备防治心血管系统炎症相关疾病药物中的用途 |
| CN103284988A (zh) * | 2012-02-24 | 2013-09-11 | 复旦大学 | 炔丙基半胱氨酸及其类似物在制备治疗免疫相关炎症疾病药物中的用途 |
| CN111544426A (zh) * | 2019-02-12 | 2020-08-18 | 复旦大学 | 炔丙基半胱氨酸及其在制备新靶点药物中的用途 |
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