DNA-encoded chemical library (DEL) technology is an important tool for early drug discovery. However, making high-quality and chemically diverse DELs is still difficult. Problems such as low reaction yields, limited control over chemical selectivity, and damage to DNA from harsh reaction conditions can reduce library quality and make drug discovery less effective.
In this work, we show that designed enzymes can help build diverse molecules directly on DNA under mild conditions. We developed an enzyme system using CoA ligases and modified N-acyl-transferases (NATs). This system enabled a wide range of amide formations on DNA (over 120 examples) and helped identify enzyme features that improve compatibility with DNA.

This work was carried out in the group of Prof. Dr. Rebecca Buller.

References:

• D. Schaub, A. Lessing, F. Meyer, M. Eichenberger, G. von Haugwitz, P. Stockinger, A. Gloger, J. Scheuermann, R. Buller;
  "A tailored enzyme cascade facilitates DNA-encoded library technology and gives access to a broad substrate scope"
  ResearchSquare, 2025, preprint; doi:10.21203/rs.3.rs-7598475/v1.
• D. Schaub, A. Lessing, G. von Haugwitz, F. Meyer, J. Scheuermann, R. Buller;
  "Towards the Chemoenzymatic Synthesis of DNA-Encoded Libraries"
  ACS Central Science, 2026, 12(1), 28-39; doi:10.1021/acscentsci.5c01516.