J Med Chem. 2019 Oct 24;62(20):9188-9200. doi: 10.1021/acs.jmedchem.9b01108. Epub 2019 Oct 8.
We have recently investigated the reactivity of aryl-fluorosulfates as warheads to form covalent adducts with Lys, Tyr, and His residues. However, the rate of reaction of aryl-fluorosulfates seemed relatively slow, putting into question their effectiveness to form covalent adducts in cell. Unlike the previously reported agents that targeted a relatively remote Lys residue with respect to the target's binding site, the current agents were designed to more directly juxtapose an aryl-fluorosulfate with a Lys residue that is located within the binding pocket of the BIR3 domain of X-linked inhibitor of apoptosis protein (XIAP). We found that such new agents can effectively and rapidly form a covalent adduct with XIAP-BIR3 in vitro and in cell, approaching the rate of reaction, cellular permeability, and stability that are similar to what attained by acrylamides when targeting Cys residues. Our studies further validate aryl-fluorosulfates as valuable Lys-targeting electrophiles, for the design of inhibitors of both enzymes and protein-protein interactions.
我们最近研究了芳基氟硫酸酯作为弹头与赖氨酸（Lys）、酪氨酸（Tyr）和组氨酸（His）残基形成共价加合物的反应性。然而，芳基氟硫酸酯的反应速率似乎相对较慢，这使得它们在细胞中形成共价加合物的有效性受到质疑。与之前报道的针对靶结合位点相对较远的赖氨酸残基的试剂不同，当前的试剂设计为更直接地将芳基氟硫酸酯与位于凋亡蛋白抑制因子（XIAP）的 BIR3 结构域结合口袋内的赖氨酸残基并置。我们发现，这些新型试剂可以有效地快速在体外和细胞内与 XIAP-BIR3 形成共价加合物，其反应速率、细胞通透性和稳定性与针对半胱氨酸残基的丙烯酰胺相似。我们的研究进一步验证了芳基氟硫酸酯作为有价值的赖氨酸靶向亲电试剂，可用于设计酶和蛋白质-蛋白质相互作用的抑制剂。
