Gentle rather than harmful: Using tailored enzymes, the researchers are constructing DNA-encoded chemical libraries under mild, water-based conditions. Because the sensitive DNA barcodes remain intact during this process, the search for new potential bioactive compounds is facilitated.
Image Credit: © University of Bern
Scientific Frontline: Extended "At a Glance" Summary: Enzymatic Synthesis of DNA-Encoded Libraries
The Core Concept: Researchers have developed a gentle, water-based method for assembling massive collections of potential drug candidates without damaging their molecular DNA "barcodes." This technique utilizes engineered enzymes instead of harsh synthetic chemicals to construct small-molecule libraries.
Key Distinction/Mechanism: Traditional DNA-encoded libraries (DELs) rely on chemical reactions that can degrade the sensitive DNA sequences used to tag and identify molecular compounds. The new method bypasses this limitation by employing customized natural catalysts—specifically, CoA ligases and N-acyltransferases—that facilitate precise molecular assembly under mild, aqueous conditions.
Major Frameworks/Components:
- DNA-Encoded Libraries (DELs): Massive collections of small molecules where each compound is tagged with a unique, short DNA sequence acting as an identifiable barcode.
- Protein Engineering: The precise adaptation of naturally occurring enzymes, allowing them to process bulky, DNA-barcoded molecules that are otherwise difficult to synthesize.
- Enzymatic Cascade: A sequential, continuous biological production line utilizing CoA ligases and N-acyltransferases to carry out multiple reaction steps in succession.
- Chemoenzymatic Synthesis: The integration of enzymatic reactions with classical chemical methods to assemble more than 120 diverse molecular structures directly on the DNA.
Branch of Science: Biochemistry, Pharmaceutical Sciences, Biocatalysis, and Molecular Biology.
Future Application: Researchers plan to extend this methodology to additional enzyme classes, further broadening the structural diversity of molecules accessible in early-stage pharmaceutical screening.
Why It Matters: Expanding the chemical diversity of DELs under mild conditions accelerates drug discovery, reduces operational costs, and provides a highly sustainable, resource-efficient alternative to traditional pharmaceutical manufacturing processes.
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| (Left to Right) Prof. Dr. Rebecca Buller, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern Photo Credit: © Courtesy of R. Buller Daniela Schaub, Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern Photo Credit: © Courtesy of D. Schaub |
Developing a new drug often takes many years. First, researchers must identify potential active ingredients that precisely target a specific site in the body—typically a protein that plays a central role in a disease. This search is particularly time-consuming for traditional small-molecule drugs, which make up most medications taken in tablet form. The goal is to find small molecules that bind specifically to their target protein in the body and, as far as possible, affect only that target. Finding such molecules is a particularly difficult challenge in research. One way to tackle it is through DNA-encoded libraries (DELs), essentially barcoded drug libraries. Researchers synthesize an enormous number of different small molecules and label each one with a “barcode” consisting of a short DNA sequence. This makes it possible to build massive collections of molecules and test them all at once to see which one binds best to a disease-relevant protein. The DNA barcode then allows researchers to identify which molecules are promising drug candidates—much like scanning a barcode at a store checkout.
A key problem with this technology, however, is that many of the chemical reactions used to create such libraries are too “harsh” for the sensitive DNA labels and can damage them. Once the barcodes are damaged, they no longer function properly, and the results become unreliable. In practice, this means that researchers can synthesize only those molecules that do not harm the DNA, leaving many interesting molecular structures out of reach.
A research team led by Professor Rebecca Buller of the Department of Chemistry, Biochemistry, and Pharmaceutical Sciences (DCBP) at the University of Bern has now found a way around this problem. In collaboration with the research group led by Professor Jörg Scheuermann at ETH Zurich and the Zurich University of Applied Sciences (ZHAW), the team used a special method to synthesize more than 120 diverse DNA-barcoded molecules under mild, water-based conditions without damaging the barcodes. In the long term, this could help accelerate the search for new drugs while also making the process more resource-efficient. The study, supported by the Swiss National Science Foundation (SNSF) as part of a Sinergia project, was published in Nature Catalysis.
Nature’s Catalysts Instead of DNA-Harming Chemicals
To develop a gentle method for producing DNA-encoded libraries, the researchers turned to two types of enzymes: so-called CoA ligases and specially developed N-acyltransferases. Enzymes are natural “tools” for chemical reactions. “Enzymes are nature’s catalysts: they accelerate reactions, work very precisely, and function in water under very mild conditions,” explains Rebecca Buller, a 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 producing DNA-encoded libraries. The researchers then combined the two enzymes so that they carried out several reaction steps in sequence, much like a small production line. In the next step, the team linked the enzymatic reactions with classical chemical methods to assemble the DNA-encoded library.
New Properties Thanks to Protein Engineering
With this new sequence of reaction steps and the combination of enzymatic and chemical methods, the researchers assembled more than 120 diverse molecular structures directly on the DNA. “We achieved this under mild, water-based conditions and without damaging the sensitive barcodes,” says Buller. Daniela Schaub, one of the two lead authors of the study and a researcher at the DCBP, adds, “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.”
The study shows 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 them well suited as gentle tools for producing DNA-encoded libraries and further expanding their diversity.
More Environmentally Friendly, Cost-Effective, and Efficient
DNA-encoded libraries are among the most important tools in early-stage drug discovery today. “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,” Buller emphasizes. “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.
Published in journal: Nature Catalysis
Authors: Daniela Schaub, Alice Lessing, Fabian Meyer, Peter Stockinger, Miquel Estévez-Gay, Michael Eichenberger, Gerlis von Haugwitz, Andreas Gloger, Jörg Scheuermann, and Rebecca Buller
Source/Credit: University of Bern
Edited by: Scientific Frontline
Reference Number: bchm071726_01
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