多药理学重定向方法确定已批准的药物作为Mycobacterium tuberculosis的潜在抑制剂
Jasdeep Singh1,2, Neha Quadir3, Shubham Vashishtha4
1Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology-Delhi, New Delhi, India.
The Biochemical journal
|June 12, 2023
概括
这项研究重新利用了Anidulafungin,Azilsartan和Degarelix等现有的药物来对抗耐药结核病 (TB). 这些重新设计的药物显示出抑制Mycobacterium tuberculosis生长和复制的潜力,为结核病治疗提供了新的途径.
科学领域:
- 微生物学 微生物学
- 药物发现 药物发现 药物发现
- 计算生物学 计算生物学
背景情况:
- 由Mycobacterium tuberculosis (M. tb) 引起的结核病 (TB) 是主要的传染病死亡原因.
- 多药耐药 (MDR) 和极度耐药 (XDR) 菌株的增加需要新的治疗策略.
- 药物再利用提供了一种有希望的方法,可以有效地识别新的抗结核病药物.
研究的目的:
- 通过重新使用FDA批准的药物来确定治疗耐药结核病的潜在候选药物.
- 通过药物重新定位策略,研究对必不可少的M. tb蛋白质的多药学向.
- 评估已识别的候选药物对M.结核病生长和复制的疗效.
主要方法:
- 选择了四种必不可少的M. tb蛋白质:PpiB,MoxR1,Ripa和S-adenosyl依赖的甲基转移酶 (sMTase).
- 在FDA批准的药物对选择的M. tb标的in silico选,使用基于复合受体模板的方法和分子动力学模拟.
- 实验验证包括异热定位热量计 (ITC),细胞基检测针对M. tb H37Ra,以及对待细菌的地形评估.
主要成果:
- 确定Anidulafungin,Azilsartan和Degarelix作为潜在的药物候选剂,以M. tb蛋白为向.
- ITC证实了这些药物的高亲和度结合到向蛋白质,干扰MoxR1和RipA蛋白质与蛋白质的相互作用.
- 基于细胞的测试表明了这些药物对M. tb生长的抑制潜力,在治疗的细菌中观察到形态异常.
结论:
- 重新设计的药物Anidulafungin,Azilsartan和Degarelix显示出作为抗菌菌剂对抗耐药结核病菌株的承诺.
- 这些候选物质可以干扰基本的M. tb过程,包括蛋白质折叠,复制和宿主免疫调节.
- 这些已识别的化合物可以作为开发下一代抗结核病治疗药物的支架,向耐药菌株.
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