CN109771420A - 2-（2-噻唑基）乙酸乙酯在抗结核分枝杆菌感染中的医药用途 - Google Patents
2-（2-噻唑基）乙酸乙酯在抗结核分枝杆菌感染中的医药用途 Download PDFInfo
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Abstract
本发明公开了2‑(2‑噻唑基)乙酸乙酯(结构如下)，对野生型及突变型核糖体蛋白S1(RpsA)具有抑制作用，进而用于制备抗结核分枝杆菌感染——尤其是吡嗪酰胺耐药的结核分枝杆菌感染的药品的用途。
Description
技术领域
本发明涉及药学领域，具体涉及2-(2-噻唑基)乙酸乙酯在抗结核分枝杆菌感染及吡嗪酰胺耐药的结核分枝杆菌感染中的医药用途。
背景技术
结核分枝杆菌感染引起的相关疾病如肺结核、淋巴结核、肠结核等，在全球流行广泛。吡嗪酰胺(PZA)作为抗结核分枝杆菌感染的一线药物，与其它一线药物如乙胺丁醇、利福平、异烟肼联用时，能有效缩短治疗周期。但随着PZA耐药问题的加重，人们对于新型抗结核分枝杆菌感染的药物需求日益急迫。2011年Science研究成果提出，PZA在体内经吡嗪酰胺酶(PZase)水解为吡嗪酸(POA)后，抑制了结核分枝杆菌的核糖体蛋白S1(RpsA)，进而阻止了结核分枝杆菌的反式翻译过程，达到抗结核分枝杆菌感染的目的。
此外，RpsA可作为抗结核分枝杆菌感染，尤其是抗吡嗪酰胺耐药结核分枝杆菌感染的理想靶标。一方面，根据临床统计结果，在吡嗪酰胺耐药的部分结核分枝杆菌菌株中，RpsA会发生438号丙氨酸缺失突变，进而POA无法抑制RpsA而失去药效；另一方面，结核分枝杆菌的RpsA与人及其它哺乳动物的蛋白同源性很低，其抑制剂将对结核分枝杆菌具有特异性。
薄层干涉实验(BLI)可以通过检测膜厚度改变而引起的光强度变化，确认膜上蛋白与配体发生了相互作用。不同浓度的配体与固定在膜上的蛋白作用时，呈现出不同程度的吸附与解离行为，据此可以拟合出复合物的解离常数值。
而核磁滴定实验，是进一步确定蛋白与配体相互作用的结构生物学手段。在1H-15N异核单量子相关谱(1H-15N HSQC)中，随着配体的加入，配体作用位点及其附近的氨基酸对应的峰将发生展宽或位移，进而可以明确蛋白与配体的相互作用。
发明内容
本发明的目的在于，提供2-(2-噻唑基)乙酸乙酯在抗结核分枝杆菌感染及吡嗪酰胺耐药的结核分枝杆菌感染中的医药用途。
首先，本发明提供的2-(2-噻唑基)乙酸乙酯具有如下结构式，为2-(2-噻唑基)乙酸乙酯，或其药学上可接受的盐，或其前体药物或其前体药物的药学上可接受的盐；
进一步的，所述2-(2-噻唑基)乙酸乙酯在抗结核分枝杆菌感染中的新医药用途，为其通过作用于野生型或突变型RpsA，可用于制备抗结核分枝杆菌感染——尤其是吡嗪酰胺耐药的结核分枝杆菌感染的药品；
更进一步的，所述的抗结核分枝杆菌感染和抗吡嗪酰胺耐药的结核分枝杆菌感染的药品，含有2-(2-噻唑基)乙酸乙酯、或其药学上可接受的盐、或其前体药物、或其前体药物的药学上可接受的盐以及其它药学上可接受的载体；
更进一步的，所述的抗结核分枝杆菌感染和抗吡嗪酰胺耐药的结核分枝杆菌感染的药品，其剂型为：固体剂型、液体剂型、气体剂型以及半固体剂型。
更进一步的，所述的抗结核分枝杆菌感染和抗吡嗪酰胺耐药的结核分枝杆菌感染的药品，含有的其它药学上可接受的载体是指：稀释剂、填充剂、赋形剂、粘合剂、湿润剂、崩解剂、表面活性剂、吸收促进剂、润滑剂或吸附载体。
附图说明
图为2-(2-噻唑基)乙酸乙酯的核磁滴定情况，上图为峰高增加的情况，下图为峰移动的情况。
具体实施方式
下述非限制性实施例可以使本领域相关人员更全面地理解本发明，但不以任何方式限制本发明。
实施例：通过薄层干涉实验拟合2-(2-噻唑基)乙酸乙酯与野生型RpsA[MtRpsA(285-476)]及突变型RpsA[MtRpsA(285-476)d438A]的解离常数，并通过核磁滴定实验进一步验证相互作用。
化合物与试剂：
主要试剂：生物素化MtRpsA(285-476)的PBS7.6溶液、生物素化MtRpsA(285-476)d438A的PBS7.6溶液、Dip and ReadTM Super Streptavidin(SSA)Biosensors、15N标记的MtRpsA(285-438)的PBS 6.0溶液、DMSO、2-(2-噻唑基)乙酸乙酯的100％DMSO储液。
主要仪器：Octet@RED96(Pall@Fortebio@)、AVANCE III 850MHz核磁共振谱仪(Bruker)。
1.解离常数(Kd)测定
实验过程：借助Octet@RED96，使一例SSA探针A1依次经过如下步骤：蛋白固定、基线平衡、待测分子结合、待测分子解离，其中结合与解离步骤共重复4次，分别对应4个浓度的小分子溶液。所有样品均加入在96孔板，体积为300μl。蛋白固定采用含有75μg/ml对应蛋白的含5％DMSO的PBS7.6溶液，基线平衡与分子解离过程均采用5％DMSO的PBS7.6溶液；小分子结合过程的2-(2-噻唑基)乙酸乙酯浓度分别为3.13μM、6.25μM、12.5μM、25.0μM，且对应溶液均为5％DMSO的PBS7.6溶液。同时以另一SSA探针A2重复上述过程，但以5％DMSO的PBS7.6溶液替换蛋白固定溶液，以扣除非特异性吸附影响。此外，采用另两例SSA探针B1与B2，检测过程同先前两例探针，但所有过程均在5％DMSO的PBS7.6溶液中进行，以扣除探针、仪器带来的系统误差。
数据处理：采用仪器对应的软件进行处理与拟合。首先进行误差的扣除，响应信号＝(A1-A2)-(B1-B2)，其中A1、A2、B1、B2为前述四只SSA探针的响应信号。而后以baseline进行对齐，并以baseline进行内部纠正。最后以Global方式进行拟合，获得Kd与其误差。
结果：2-(2-噻唑基)乙酸乙酯与野生型RpsA[MtRpsA(285-476)]及突变型RpsA[MtRpsA(285-476)d438A]的解离常数分别为：2.1μM、4.8μM，误差分别为0.20μM、0.25μM，表明2-(2-噻唑基)乙酸乙酯与两例蛋白具有较强的相互作用。
2.化合物与蛋白的核磁滴定验证
实验过程：在两只5mm核磁管中加入500μl含200μM 15N标记的MtRpsA(285-438)蛋白、5％DMSO、10％D2O的PBS 6.0溶液，其中一只加入15μl DMSO作为空白对照，采集1H-15NHSQC图谱；另一只加入15μl2-(2-噻唑基)乙酸乙酯的100mM DMSO溶液，以相同参数采集1H-15N HSQC图谱。采集参数如下：采用hsqcetfpf3gp脉冲程序，采样温度为298K，扫描次数为8次，氢维谱宽为12.9713ppm，氮维谱宽为29.0000ppm，氢维中心频率为4.696ppm。谱图经处理变换后，标定谱峰对应的氨基酸，输出各峰的位置与高度。展宽情况以Hfree/Hcomplex评价，Hfree为无化合物时的峰高，Hcomplex为加入小分子后的峰高；位移情况以Δδ＝(ΔδH 2+(ΔδN-H/5)2)1/2评价，ΔδH为氢维的位移，ΔδN-H为氮维的位移。
实验结果如说明书附图，峰高度与峰位置均发生了变化，表明2-(2-噻唑基)乙酸乙酯与蛋白确实发生了相互作用。并且，由于峰同时发生了位移与展宽，表明Kd＜10μM，与薄层干涉实验结果一致。
Claims (4)
1.2-(2-噻唑基)乙酸乙酯在抗结核分枝杆菌感染，特别是抗耐吡嗪酰胺结核分枝杆菌感染中的医药用途，其特征在于其具有如下结构，为2-(2-噻唑基)乙酸乙酯；
2.抗结核分枝杆菌药物，作用于野生型或突变型结核分枝杆菌核糖体蛋白S1(RpsA)，其特征在于含有权利要求1中所述2-(2-噻唑基)乙酸乙酯以及一种或多种药学上可接受的载体。
3.如权利要求2中所述的抗菌药物，其特征在于所述药学上可接受的载体是指：稀释剂、填充剂、赋形剂、粘合剂、湿润剂、崩解剂、表面活性剂、吸收促进剂、润滑剂或吸附载体。
4.如权利要求2中所述的抗菌药物，其特征在于该药物的剂型为：片剂、丸剂、胶囊、悬浮剂、乳剂、注射剂或干粉剂。
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| R. MORY等: "Thiazoleacetic acids", 《HELVETICA CHIMICA ACTA》 * |
| YI FAN等: "Structural basis for ribosome protein S1 interaction with RNA in transtranslation of Mycobacterium tuberculosis", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
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