New chemical reaction expands the design of DNA-encoded molecular libraries

Finding new drugs requires screening vast numbers of compounds to identify those that interact with a biological target. DNA-encoded libraries (DELs) help researchers explore these large collections by attaching a short DNA sequence to each molecule, acting as a molecular barcode that allows compounds with promising properties to be identified.

Building these libraries poses a chemical challenge: the reactions used to modify molecules must preserve the DNA, which can be damaged under certain chemical conditions. New reactions that operate under mild conditions and in the presence of DNA could therefore expand the range of compounds that can be explored.

Researchers led by Manuel Nappi at the Centre for Research in Biological Chemistry and Molecular Materials (CiQUS), Universidade de Santiago de Compostela (USC), have developed a strategy to couple carbonyl compounds, such as aldehydes and ketones, with other molecules, including those containing double bonds. The reaction provides a versatile route to aliphatic alcohols, structural motifs found in many compounds of pharmaceutical interest.

The method relies on a catalyst and light to activate the starting compounds without the strongly reducing conditions that can restrict the range of compatible molecules and hinder reactions in the presence of DNA. The process works at room temperature and with a broad range of molecular partners, making it suitable for applications where sensitive chemical structures must be preserved.

From fundamental chemistry to drug discovery

The team tested the method in reactions performed on DNA, demonstrating that different molecular structures could be incorporated under conditions compatible with DNA-encoded library technology. AstraZeneca collaborated on this part of the study, helping assess the method's suitability for drug-discovery applications.

The collaboration was particularly important in testing longer DNA fragments, closer to those used in DNA-encoded libraries. Experiments with fragments 59 units long showed that the DNA was largely preserved and retained its readability. The researchers also detected very low levels of sequence changes, an essential requirement for ensuring that each molecular compound can still be correctly identified by its DNA barcode.

The results establish a new chemical approach for modifying molecules attached to DNA, expanding the methods available for building DNA-encoded libraries and supporting drug discovery.

The study, entitled Reductive Couplings Via Nucleophilic Photoactivation of Carbonyls, was published in the Journal of the American Chemical Society (JACS).

CiQUS holds the María de Maeztu Unit of Excellence accreditation and the CIGUS recognition awarded by the Xunta de Galicia. The centre also receives European Union funding through the Galicia FEDER 2021–2027 Programme.

Reference

Sai Rohini Narayanan Kolusu, Manuel Rodríguez-Martínez, Carla Aira-Rodríguez, Matteo Caldari, Gabriel Brenlla-Carballo, Ismael Amado-Amado, Emanuele Azzi, Yinan Song, Joseph Ward, Nidhal Selmi, Jesús A. Varela and Manuel Nappi. Reductive Couplings Via Nucleophilic Photoactivation of Carbonyls. Journal of the American Chemical Society, 2 September 2026, 148 (34): 37235–37244. https://doi.org/10.1021/jacs.6c12120