New High-Throughput Workflow Streamlines Building Block Conjugation for DNA-Encoded Library Synthesis
Researchers at Vipergen have developed a fast and cost-effective 96-well plate workflow for the conjugation of building blocks to DNA, streamlining the preparation of key components for DNA-encoded library (DEL) synthesis.
A critical step in DEL preparation is the conjugation of building blocks to DNA – a process that becomes increasingly time-consuming and technically demanding when scaled to the hundreds or thousands of building blocks. The new workflow, published in Bioconjugate Chemistry, addresses this directly by integrating codon ligation, ester hydrolysis, and building block conjugation into a single pot process carried out entirely in 96-well plates. By minimizing liquid transfers and handling steps, the method significantly reduces hands-on time without compromising product quality.
A central feature of the study is the systematic evaluation of two amine protecting group strategies: Boc and pNs – across 278 building blocks spanning 15 scaffold classes. While Boc protection performed well for most compounds, the authors identified several cases where switching to the milder pNs deprotection conditions proved decisive in recovering good yields, demonstrating the complementarity of the two strategies.
“We wanted a process that could handle hundreds of building blocks without becoming a bottleneck. By keeping everything in 96-well plates from start to finish, we significantly cut down hands-on time while maintaining the quality needed for DEL synthesis,” said Senior Scientist Dr. Peter Blakskjær, lead author of the study.
The practical value of the workflow was validated by incorporating all conjugates into DELs using Vipergen’s yoctoreactor platform, with DNA codon integrity confirmed by sequencing and building block identity and purity verified by HPLC-MS. Compatible with both templated and split-and-mix DEL formats, the authors also note broader relevance for the wider bioconjugation community.
Find the paper here: https://doi.org/10.1021/acs.bioconjchem.6c00010
About Vipergen:
Vipergen is a world-leading provider of small-molecule drug discovery services based on DNA-encoded library (DEL) technologies and is the first and only company capable of screening DELs inside a living cell. Vipergen provides its proprietary suite of leading-edge DEL technologies through funded discovery partnerships with leading pharmaceutical and biotechnology companies, including top pharmaceutical companies in the U.S., EU, and Japan. For more details about Vipergen and the YoctoReactor® (yR), Binder Trap Enrichment® (BTE), and Cellular Binder Trap Enrichment® (cBTE) drug discovery technology platforms, please visit www.vipergen.com.