Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces

A general strategy is described for improving the binding properties of small-molecule ligands to protein targets. A bifunctional molecule is created by chemically linking a ligand of interest to another small molecule that binds tightly to a second protein. When the ligand of interest is presented to the target protein by the second protein, additional protein–protein interactions outside of the ligand-binding sites serve either to increase or decrease the affinity of the binding event. We have applied this approach to an intractable target, the SH2 domain, and demonstrate a 3-fold enhancement over the natural peptide. This approach provides a way to modulate the potency and specificity of biologically active compounds.

本文报道了一种通用策略，用于优化小分子配体与蛋白靶点的结合性能。通过将目标配体与另一类紧密结合于第二蛋白的小分子进行化学偶联，可构建双功能分子。当第二蛋白将目标配体呈递至靶蛋白时，配体结合位点以外的额外蛋白-蛋白相互作用，可增强或削弱该结合事件的亲和力。我们将该策略应用于一个难靶向靶点——SH2结构域（SH2 domain），并证实其结合活性相较于天然肽提升了3倍。该策略为调控生物活性化合物的效价与特异性提供了可行途径。