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发现针对蛋白质衍生的电友性辅因子的强效和选择性抑制剂

Xie Wang¹, Zongtao Lin¹, Katelyn A Bustin¹

¹Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.

Journal of the American Chemical Society

|March 2, 2022

概括

研究人员开发了一种新的平台来研究以前传统方法错过的电友性辅因子,如glyoxylyl (Glox) 组. 他们发现了Glox含有SCRN蛋白的选择性抑制剂,为新的治疗策略铺平了道路.

科学领域:

生物化学
化学生物学
蛋白质组学

背景情况:

电友性辅因子,如氧 (Glox) 和 (Pyvl) 组,在生物过程中至关重要,但使用针对核友的传统基于活性的蛋白质概况 (ABPP) 方法进行研究是具有挑战性的.
反极性 (RP) - ABPP 已使电友性辅因子的鉴定成为可能,特别是 N-终端 Glox 组在secernin-3 (SCRN3) 中,但缺乏可供药理验证的选择性抑制剂.

研究的目的:

建立一个新的平台来分析核友探针对电友主链碳酸辅因子的反应性和选择性.
确定Glox和Pyvl组的选择性抑制剂,使其生物功能的研究和向治疗的开发成为可能.

主要方法:

开发和应用扩展的核友探针库,用于电友蛋白标的全蛋白质概况.
使用具有竞争力的 in vitro RP-ABPP 试验方法,使用一颗英多尔乙基探针从商业上可用的核片段中选选择性抑制剂.
使用含Glox的SCRN蛋白 (SCRN2和SCRN3) 验证抑制剂的选择性和功效的案例研究.

主要成果:

开发的平台成功地分析并证实了与各种电友蛋白目标的接触,包括SCRN2和SCRN3,两者都具有Glox组.
一种纳基衍生物被确定为含Glox的SCRN蛋白的强大和选择性抑制剂,在细胞溶解物中表现出完全的抑制,没有显著的目标外活性.
该研究证实了SCRN2中Glox组的存在,扩大了该辅因子的已知目标.

结论:

这种新开发的平台为研究电友辅助因子及其与蛋白质的相互作用提供了强大的方法.
选择性抑制剂的鉴定,如纳酸,是对依赖Glox的生物功能的药理验证的一个关键步骤.
这项工作奠定了开发新型小分子的基础,这些分子调节了治疗干预的电友依赖途径.

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