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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Adenosine Triphosphate (ATP) is crucial for enzyme activation, particularly kinases involved in diseases like cancer.
• Inhibiting ATP-dependent enzymes necessitates blocking ATP binding, leading to the development of ATP chelators.
• Existing ATP chelators utilize either zinc complexes with nitrogen ligands (e.g., 2,2';6',2″-terpyridine) for phosphate binding or phenylboronic acid for ribose diol binding.

Purpose of the Study:

• To design and synthesize a novel ATP chelation strategy by integrating two distinct binding mechanisms into a single molecular scaffold.
• To evaluate the efficacy of these combined-strategy chelators in inhibiting ATP binding with high affinity.
• To investigate the structural basis for enhanced ATP binding affinity in the novel chelators.

Main Methods:

• Peptidomimetic oligomers, known as peptoids, were synthesized to incorporate both Zn(Terpy) and phenylboronic acid (PBA) moieties.
• The binding affinity of the synthesized peptoids to ATP was determined using established methods.
• Structural studies were conducted to elucidate the spatial arrangement of the chelating groups and its effect on ATP binding.

Main Results:

• The novel peptoids incorporating both Zn(Terpy) and PBA demonstrated potent ATP binding inhibition.
• The highest observed binding affinity was K_D-ATP = 7.416 × 10^-9 M, which is four times higher than peptoids targeting only phosphates or diols.
• This affinity is at least two orders of magnitude greater than that of previously known ATP chelators.
• Structural analysis revealed that proximity of Terpy and PBA side chains enhances ATP binding affinity.

Conclusions:

• A unique and highly effective ATP chelation approach has been developed by combining phosphate and diol binding strategies within a peptoid scaffold.
• These novel peptoids represent a significant advancement in ATP binding inhibition, offering superior affinity compared to existing chelators.
• The findings provide a foundation for developing new therapeutic agents targeting ATP-dependent enzymes in various medical conditions.