Department of Chemistry, The Scripps Research Institute, La Jolla, California, USA.
Nat Chem Biol. 2010 Feb;6(2):133-9. doi: 10.1038/nchembio.281.
A small molecule that could bind selectively to and then react chemoselectively with a non-enzyme protein in a complex biological fluid, such as blood, could have numerous practical applications. Herein, we report a family of designed stilbenes that selectively and covalently modify the prominent plasma protein transthyretin in preference to more than 4,000 other human plasma proteins. They react chemoselectively with only one of eight lysine e-amino groups within transthyretin. The crystal structure confirms the expected binding orientation of the stilbene substructure and the anticipated conjugating amide bond. These covalent transthyretin kinetic stabilizers exhibit superior amyloid inhibition potency compared to their noncovalent counterparts, and they prevent cytotoxicity associated with amyloidogenesis. Though there are a few prodrugs that, upon metabolic activation, react with a cysteine residue inactivating a specific non-enzyme, we are unaware of designed small molecules that react with one lysine e-amine within a specific non-enzyme protein in a complex biological fluid.
一种小分子能够选择性地与复杂生物流体（如血液）中的非酶蛋白结合，然后选择性地进行化学反应，它可能有许多实际应用。在此，我们报告了一系列设计的二苯乙烯类化合物，它们能够选择性地和共价修饰显著的血浆蛋白转甲状腺素蛋白，而不是 4000 多种其他人类血浆蛋白。它们只与转甲状腺素蛋白的八个赖氨酸 e-氨基中的一个发生化学选择性反应。晶体结构证实了预期的二苯乙烯亚结构的结合取向和预期的连接酰胺键。与非共价类似物相比，这些共价转甲状腺素蛋白动力学稳定剂具有更高的淀粉样蛋白抑制效力，并且可以预防与淀粉样变性相关的细胞毒性。虽然有一些前药在代谢激活后与半胱氨酸残基反应，使特定的非酶失活，但我们不知道有设计的小分子能够在复杂的生物流体中的特定非酶蛋白内与一个赖氨酸 e-胺反应。
