Water‐Soluble Peptoids with Two Different Binding Sites for Strong ATP Chelation

Adenosine Triphosphate (ATP) is the activator of many enzymes, including kinases, that play a significant role in various medical conditions such as cancer. Therefore, inhibiting ATP-dependent enzymes requires to disable its binding to enzymes, and this can be done by developing potent ATP chelators. Currently, there are two main types of chelators: one that binds ATP via zinc complexes of nitrogen-based ligands, such as 2,2';6',2″-terpyridine (Terpy), which target the phosphate ligands, and another one containing phenylboronic acid (PBA) to bind the diols within the ribose. Herein, we report on a unique chelation approach that combines these two binding strategies in one scaffold; we use peptidomimetic oligomers called peptoids that incorporate both Zn(Terpy) and PBA as strong, water-soluble ATP binding inhibitors. These peptoids demonstrated high affinity to ATP, where the highest is K_D-ATP = 7.416 × 10^-9 M, four times higher than the binding affinity of peptoids targeting only phosphates or only diols, and at least two orders of magnitude higher than known ATP chelators. Structural studies indicated that positioning both Terpy and PBA side chains close together on the scaffold increased ATP binding affinity, compared to spacing them apart.