使用基于函数-第一个"侦察片段"的方法来开发对形态动态酶机械酶的共价抑制剂
Jared R Ramsey1,2, Patrick M M Shelton2, Tyler K Heiss2
1Tri-Institutional PhD Program in Chemical Biology, New York, New York 10021, United States.
Journal of the American Chemical Society
|December 22, 2023
概括
研究人员开发了一种新的方法,使用电友侦察碎片制造酶的共价抑制剂,这些酶在DNA/RNA过程和疾病中至关重要. 这种方法成功地准病毒和人体螺旋酶,提供了新的治疗策略.
科学领域:
- 生物化学和分子生物学
- 酵素学
- 药物发现
背景情况:
- 螺旋酶是必不可少的ATP依赖的机制酶,重塑核酸,在DNA/RNA代谢,转化和基因组维护中发挥关键作用.
- 功能障碍的螺旋酶涉及各种疾病,包括癌症和病毒感染,使它们成为有吸引力的治疗点.
- 由于它们的高构造动力学,开发特殊的化学抑制剂是具有挑战性的.
研究的目的:
- 探索电友"侦察碎片"对于开发对酶的共价抑制剂的有用性.
- 在形态动态机械酶中识别可用药物的基位.
- 开发一种向SARS-CoV-2 nsp13的共价抑制剂,并评估侦察碎片对人类螺旋酶的潜力.
主要方法:
- 采用功能优先策略,将酶分析与反体探针对和质谱结合起来.
- 使用从化学蛋白质组学研究中已知的侦察片段,以准螺旋酶异质位点.
- 对SARS-CoV-2 nsp13 (超级家族-1 螺旋酶) 和人类 BLM 和 WRN 螺旋酶 (超级家族-2) 的测试抑制剂有效性.
主要成果:
- 成功开发了一种选择性向SARS-CoV-2 nsp13中的基位的共价抑制剂.
- 证明侦察碎片可以抑制人类超级家族-2螺旋酶,BLM和WRN的活性.
- 验证了侦察碎片在动态酶中发现共价抑制剂起点的潜力.
结论:
- 电友侦察片段代表一种可行的策略,用于开发对像酶这样具有挑战性的酶目标的共价抑制剂.
- 这项研究提出了一种新的方法,用于识别基位,并为共价药物发现提供起点.
- 这种方法有望开发针对病毒病原体和与酶功能障碍相关的人类疾病的治疗方法.
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