Cu/Zn–ZIF: a Metal–Organic Framework for Eliminating Excessive Stimulation from Cyclic Adenosine Monophosphate (cAMP)

Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that orchestrates metabolism, gene transcription and neuronal signaling. Sustained overactivation of cAMP pathways, however, is implicated in neurodegenerative, cardiovascular and inflammatory disorders. Conventional regulation mainly relies on phosphodiesterase (PDE) inhibitors, which raise intracellular cAMP and may aggravate adverse effects when used in complex physiological environments. Here, a bimetallic zeolitic imidazolate framework, Cu/Zn-ZIF, was constructed using 2-methylimidazole as the ligand to achieve controlled hydrolysis of cAMP under near-physiological conditions. The material was synthesized by a mild water-bath method and comprehensively characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR) spectroscopy and high-performance liquid chromatography (HPLC). Under neutral pH at 37 °C, 10.0 mg of Cu/Zn-ZIF decreased the cAMP concentration in fetal bovine serum by 26.8%, effectively attenuating excessive stimulation while avoiding complete depletion of the messenger. The catalyst retained activity in cAMP-rich jujube extracts and serum, demonstrating good stability and tolerance to common interfering species in complex matrices. Kinetic analysis confirmed its nanozyme-like behavior, and the self-limited conversion was favorable for maintaining basal signaling. Density functional theory (DFT) calculations revealed that Cu centers act as the primary catalytic sites, while Zn ions stabilize the framework and assist substrate binding, thereby promoting phosphodiester bond cleavage through an adsorption–electron-transfer–hydrolysis pathway. These findings suggest that Cu/Zn-ZIF provides a robust platform for moderating pathological cAMP elevation and offer a mechanistic basis for the rational design of metal–organic framework catalysts for bio-relevant nucleotide regulation and broader biomedical applications.