A team from CiQUS, directed by Manuel Nappi, has achieved a new synthetic reaction that allows molecules to be attached to DNA. This technology is compatible with DNA-encoded compound libraries (DEL), crucial tools in the pharmaceutical industry for drug discovery, as they facilitate the analysis of large compound collections.
The construction of these libraries faces the challenge of ensuring reactions are compatible with DNA, which is sensitive to certain chemical conditions. The new strategy developed by Nappi's team allows the joining of carbonyl compounds (aldehydes and ketones) with other molecules, such as those containing double bonds, yielding aliphatic alcohols, a structure present in many pharmaceutical compounds. The process is carried out at room temperature and with light, without strong reducing conditions, making it suitable for sensitive systems.
Collaboration with AstraZeneca was fundamental in evaluating the method's compatibility with longer DNA fragments, similar to those used in DEL applications. Assays confirmed that the DNA is largely preserved and maintains its readability, with a very low rate of sequence changes, essential aspects for correctly identifying each compound.
This new chemical strategy is transferable to DNA synthesis, offering a new tool for drug discovery. The work was published in the journal Journal of the American Chemical Society (JACS) under the title ‘Reductive Couplings Via Nucleophilic Photoactivation of Carbonyls’. CiQUS holds the María de Maeztu seal and the CIGUS recognition from the Xunta de Galicia.
