Reimagine biocatalysis: Turning DNA phosphates into chiral catalysts

Chemists at the National University of Singapore (NUS) have found a new use for deoxyribonucleic acid (DNA), not just as genetic material, but as a tool for more efficient production of medicinal compounds. Certain parts of DNA, called phosphates, can act like tiny “hands” that guide chemical reactions to selectively produce the desired mirror-image version of a compound.

Many medicinal compounds are chiral, meaning they come in two mirror-image forms, like right and left hands, that can behave very differently in the body. This is an important aspect because many drugs only work in one of their mirror-image forms. For example, the “right-handed” version might cure a disease, while the “left-handed” one could be ineffective or even harmful. Making the correct version is often challenging, but this new DNA-based approach could make the process simpler and more environmentally friendly.

In living organisms, DNA and proteins naturally attract each other because DNA’s phosphate groups are negatively charged, while many protein building blocks are positively charged. The research team, led by Assistant Professor ZHU Ru-Yi from the Department of Chemistry at NUS explored whether this same attraction could be used to control and direct chemical reactions to produce the required products.

They discovered that certain phosphate groups in DNA can attract and guide positively charged reactants during a chemical reaction. This is similar to a magnet gently pulling a metal bead into the correct orientation. This “ion-pairing” effect holds the reactants close and in a particular orientation, steering the reaction in a specific way to produce only one mirror-image product. The team demonstrated this effect across several different types of chemical reactions.

To understand exactly which parts of DNA were responsible, the researchers developed a new experimental method called “PS scanning”. The researchers systematically replaced individual phosphates along DNA with closely related look‑alikes, then repeated the reactions. If changing a particular position caused the selectivity to drop, it indicated that the original phosphate at that site was important for guiding the reaction. Computer simulations were carried out in collaboration with Professor ZHANG Xinglong from The Chinese University of Hong Kong to validate these findings.

The research was published in the scientific journal Nature Catalysis.

Ionic interactions involving DNA phosphates are ubiquitous and essential across all kingdoms of life. In this study, their catalytic potential has been demonstrated in a variety of asymmetric transformations through ion-pairing interactions in water. DNA’s negatively charged phosphates can pair with positively charged reagents, allowing DNA to act as a chiral catalyst in water. [Credit: Nature Catalysis]

Assistant Professor Zhu said, “Nature never uses DNA phosphates as catalysts, but we have shown that if designed properly, they can act like artificial enzymes.”

“Beyond being a conceptual breakthrough, this method could make chemical manufacturing more sustainable and environmentally friendly, especially for producing complex, high-value molecules used in pharmaceutical products,” added Assistant Professor Zhu.

Looking ahead, the team plans to explore more ways to use DNA phosphates to create chiral (mirror-image) compounds for drug development.

Reference
Li Z; Zheng Y*; Zhao Q; Li Y; Yap A; Zhang X*; Zhu R-Y*, “DNA Phosphates are Effective Catalysts for Asymmetric Ion-Pairing DNA Catalysis” Nature Catalysis DOI: 10.1038/s41929-025-01437-z Published: 2025.