Gentle method for discovering new drugs developed

Researchers at the University of Bern, in collaboration with ETH Zurich and the Zurich University of Applied Sciences (ZHAW), have developed a gentle, enzyme-based method to discover new small-molecule drug candidates in Switzerland.

By using Nature’s catalysts instead of harsh chemicals, the team can build large, diverse DNA-encoded libraries of potential bioactive compounds in water and under mild conditions, helping to make early-stage drug discovery more efficient, cost-effective, and resource-friendly.

Rethinking small-molecule drug discovery with DNA-encoded libraries

Developing a new drug often takes many years, especially for traditional small-molecule drugs that are usually taken in tablet form. A crucial first step is to identify active ingredients that precisely target a specific site in the body, typically a protein that plays a central role in a disease. Researchers aim to find small molecules that bind selectively to their target protein and minimize off-target effects, but this search is particularly challenging.

DNA-encoded libraries (DELs) have become a powerful tool in this process. In DEL technology, scientists synthesize an enormous number of different small molecules and attach a unique DNA ‘barcode’ to each one. This barcode, a short DNA sequence, identifies the molecule much like scanning a barcode at a store checkout. These DNA-barcoded molecules can then be screened in parallel to determine which ones bind best to a disease-relevant protein, revealing promising drug candidates.

However, many of the chemical reactions traditionally used to build DELs are too harsh for the sensitive DNA tags and can damage them. Once the barcodes are compromised, they no longer function reliably, and the screening results become uncertain. As a result, only molecules that can be synthesized without harming DNA are typically included, leaving many potentially valuable molecular structures inaccessible.

Enzyme-powered chemistry protects DNA barcodes

A research team led by Prof. Dr. Rebecca Buller from the Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) at the University of Bern has now demonstrated a way around this limitation. Working with the research group of Prof. Dr. Jörg Scheuermann at ETH Zurich and colleagues at ZHAW, the team used a special enzymatic method to synthesize more than 120 diverse DNA-barcoded molecules under mild, water-based conditions without damaging the DNA barcodes.

The study, supported by the Swiss National Science Foundation (SNSF) as part of a Sinergia project and published in Nature Catalysis, shows how enzyme-catalyzed reactions can expand the chemical space accessible to DNA-encoded libraries while preserving barcode integrity. In the long term, this approach could accelerate the search for new drugs and make the underlying chemistry more resource efficient.

Nature’s catalysts replace DNA-harming reactions

To develop a gentle method for producing DNA-encoded libraries, the researchers turned to two types of enzymes: CoA ligases and specially developed N-acyltransferases. Enzymes are natural tools for catalyzing chemical reactions.

“Enzymes are Nature’s catalysts: they accelerate reactions, work very precisely, and function in water under very mild conditions,” explains Rebecca Buller, professor at the DCBP at the University of Bern and lead author of the study.

Using protein engineering, the team tailored these enzymes to make them particularly well-suited for building DNA-encoded libraries. They then combined the two enzyme classes so that they carried out several reaction steps in sequence, functioning like a small production line. In a subsequent step, the researchers linked the enzymatic reactions with classical chemical methods to assemble the DNA-encoded library directly on the DNA.

Protein engineering enables new molecular diversity on DNA

With this new sequence of reaction steps and the combination of enzymatic and chemical methods, the researchers assembled over 120 diverse molecular structures directly on DNA under mild, water-based conditions and without damaging the sensitive barcodes.

“Enzymes have long been known as versatile tools for making small molecules and are widely used in industry. Yet until now they have hardly been used to build DNA-encoded libraries,” notes Daniela Schaub, one of the two lead authors of the study and a researcher at the DCBP.

The study demonstrates that, with the help of protein engineering, enzymes can be adapted to process molecules that already carry large, bulky DNA barcodes, something that was previously very difficult. This makes engineered enzymes well-suited as gentle tools for producing DNA-encoded libraries and for further expanding their structural diversity.

Towards more sustainable and efficient drug discovery

DNA-encoded libraries are among the most important tools in early-stage drug discovery. By increasing the chemical diversity of these libraries and enabling reactions under mild, water-based conditions, the new method offers scientific, economic, and sustainability benefits.

“Our basic research and the newly developed method help increase the chemical diversity of these libraries while making the underlying chemistry more efficient and potentially more resource-efficient,” says Schaub.

“Developing new drugs is a lengthy and costly process,” emphasizes Buller. “If we can use methods in the early stages of drug discovery that allow for greater chemical diversity and function under mild, water-based conditions, that is a win – scientifically, economically, and in terms of sustainability.”

Next, the team plans to extend the method to additional enzyme classes and further optimize the enzymes, broadening the range of molecules accessible in DNA-encoded libraries and supporting the discovery of future therapeutics.

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