Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in noncovalent interactions with proteins. Thioether-containing macrocycles are also attracting attention as protein–protein interaction (PPI) inhibitors. Here, we used a model PPI between α-helical mixed lineage leukemia (MLL) protein and kinase-inducible domain interacting (KIX) domain to evaluate oxidation effects on sulfurcontaining macrocycle structure, stability, and protein affinity. Desolvation effects from various polarity states were evaluated computationally and experimentally at the side chain, amino acid, and peptide level. Sulfur-containing side chains spanned polarity ranges between all-hydrocarbon and lactam bridges for modulating solubility, cellular uptake, and affinity. Helical propensity studies showed that, although oxidized sulfur-containing side chains could be tolerated, conformational effects were sequence-dependent. In some cases, proteolytic stability, binding capacity with KIX, and increased helicity were obtained as first steps toward developing PPI inhibitors.

中文翻译：

---

调节硫醚桥肽大环上的硫氧化态，以调节蛋白质相互作用。

尽管具有多种理化特性，但硫醚，亚砜和sulf离子均与蛋白质发生非共价相互作用。含硫醚的大环化合物作为蛋白质间相互作用（PPI）抑制剂也引起了人们的注意。在这里，我们使用α-螺旋混合谱系白血病（MLL）蛋白和激酶诱导型结构域相互作用（KIX）结构域之间的模型PPI来评估对含硫大环结构，稳定性和蛋白质亲和力的氧化作用。在侧链，氨基酸和肽水平上，通过计算和实验评估了来自各种极性状态的去溶剂化作用。含硫的侧链跨越全烃和内酰胺桥之间的极性范围，以调节溶解度，细胞摄取和亲和力。螺旋倾向研究表明，尽管可以容忍氧化的含硫侧链，但构象效应是序列依赖性的。在某些情况下，获得蛋白水解稳定性，与KIX的结合能力以及增加的螺旋度是开发PPI抑制剂的第一步。