NCCR Chemical Biology and University of Geneva, 1211 Geneva, Switzerland; University of Lausanne (UNIL), Lausanne, Switzerland.
Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland.
Bioorg Med Chem Lett. 2022 Sep 1;71:128766. doi: 10.1016/j.bmcl.2022.128766. Epub 2022 May 7.
Here we draw insights from the latest serendipitous findings made on the opposing roles of a proposed drug-target protein Keap1. We weigh up how natural reactive electrophiles and electrophilic small-molecule drugs in clinical use directly impinge on seemingly conflicting, yet both Keap1-electrophile-modification-dependent, cell-survival- vs. cell-death-promoting behaviors. In the process, we convey how understanding reactive chemical-signal regulation at the single-protein-specific level is an enabling necessity in deconstructing otherwise intricate reactive-small-molecule-responsive cellular pathways. We hope this opinion piece further spurs the broader interests of basic and pharmaceutical research communities toward better understanding of molecular mechanisms underpinning reactive small-molecule-regulated signaling subsystems.
在这里，我们从最近关于拟议药物靶标蛋白 Keap1 的相反作用的偶然发现中汲取了一些见解。我们权衡了临床使用的天然反应性亲电试剂和亲电小分子药物如何直接影响看似相互矛盾但又都依赖于 Keap1-亲电修饰的细胞存活与促进细胞死亡的行为。在这个过程中，我们传达了在单个蛋白质特异性水平上理解反应性化学信号调节是分解复杂的反应性小分子反应性细胞途径的必要条件。我们希望这篇观点文章能进一步激发基础研究和制药研究界更广泛的兴趣，以更好地理解反应性小分子调节的信号子系统的分子机制。
