Salimizand Himen, Jamehdar Saeid Amel, Nik Leila Babaei, Sadeghian Hamid
Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Antimicrobial Resistance Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Iran J Basic Med Sci. 2017 Jun;20(6):722-728. doi: 10.22038/IJBMS.2017.8859.
Tuberculosis (TB), a disease caused by (), stayed a global health thread with high mortality rate. Since TB has a long-term treatment, it leads high risk of drug resistant development, and there is an urgent to find new drugs. The aim of this study was designing new inhibitors for a new drug target, iron dependent regulator, IdeR.
Based on the interaction most populated amino acids of IdeR to the related gene operators, 50 short peptides were modeled. Bonding affinity of short peptides toward DNA were studied by docking. Top 10 best predicted bonding affinity were selected. DNA binding assay, microplate alamar blue assay, colony counting, quantitative real time- PCR (qRT-PCR) of IdeR corresponding genes, cell wall-associated mycobactin and whole-cell iron estimation were done to prove the predicted mechanism of potent constructs.
Amongst the 10 synthesized short peptide candidates, glycine-valine-proline-glycine (GVPG) and arginine-proline-arginine (RPR) inhibited at 200 μM concentration. qRT-PCR showed 58-fold over expression that resulted in growth inhibition. Cell wall-associated mycobactin and whole-cell iron estimation confirmed the results of qRT-PCR.
We introduced two new lead compounds to inhibit that are promising for the development of more potent anti-tubercular therapies.
结核病（TB）是由（）引起的一种疾病，仍然是全球高死亡率的健康威胁。由于结核病治疗周期长，导致耐药性发展的风险很高，因此迫切需要寻找新药。本研究的目的是为一种新的药物靶点——铁依赖性调节因子（IdeR）设计新的抑制剂。
基于IdeR与相关基因操纵子相互作用最丰富的氨基酸，构建了50个短肽模型。通过对接研究短肽与DNA的结合亲和力。选择预测结合亲和力最高的前10个。进行DNA结合测定、微孔板阿尔玛蓝测定、菌落计数、IdeR相应基因的定量实时聚合酶链反应（qRT-PCR）、细胞壁相关分枝杆菌素和全细胞铁估计，以验证有效构建体的预测机制。
在10个合成的短肽候选物中，甘氨酸-缬氨酸-脯氨酸-甘氨酸（GVPG）和精氨酸-脯氨酸-精氨酸（RPR）在200μM浓度下具有抑制作用。qRT-PCR显示表达量增加58倍，导致生长抑制。细胞壁相关分枝杆菌素和全细胞铁估计证实了qRT-PCR的结果。
我们引入了两种新的先导化合物来抑制（），这对于开发更有效的抗结核治疗方法很有前景。
